Next Article in Journal
The Convergence of the Hedgehog/Intein Fold in Different Protein Splicing Mechanisms
Previous Article in Journal
Genome-Wide Analysis of the Five Phosphate Transporter Families in Camelina sativa and Their Expressions in Response to Low-P
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
IJMS
Volume 21
Issue 21
10.3390/ijms21218366
ijms-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

Application of Mesenchymal Stem Cells in Inflammatory and Fibrotic Diseases

by
Jae-Sung Ryu
1,2,†,
Eun-Jeong Jeong
3,4,†,
Jong-Yeup Kim
1,2,
Soon Ju Park
3,5,
Won Seok Ju
3,5,
Chang-Hyun Kim
6,
Jang-Seong Kim
4,7 and
Young-Kug Choo
3,5,*
1
Department of Otorhinolaryngology-Head and Neck Surgery, College of Medicine, Konyang University, Daejeon 35365, Korea
2
Department of Biomedical Informatics, College of Medicine, Konyang University, Daejeon 35365, Korea
3
Department of Biological Science, College of Natural Sciences, Wonkwang University, Iksan 54538, Korea
4
Biotherapeutics Translational Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 34141, Korea
5
Institute for Glycoscience, Wonkwang University, Iksan 54538, Korea
6
College of Medicine, Dongguk University, Goyang 10326, Korea
7
Department of Functional Genomics, University of Science and Technology (UST), Daejeon 34141, Korea
*
Author to whom correspondence should be addressed.
†
These authors contributed equally to this work.
Int. J. Mol. Sci. 2020, 21(21), 8366; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21218366
Submission received: 12 October 2020 / Revised: 29 October 2020 / Accepted: 5 November 2020 / Published: 7 November 2020
(This article belongs to the Section Biochemistry)
Browse Figure
Review Reports Versions Notes

Abstract

:
Mesenchymal stem cells (MSCs) are multipotent stem cells that can be isolated from various tissues in the adult body. MSCs should be characterized by three criteria for regenerative medicine. MSCs must (1) adhere to plastic surfaces, (2) express specific surface antigens, and (3) differentiate into mesodermal lineages, including chondrocytes, osteoblasts, and adipocytes, in vitro. Interestingly, MSCs have immunomodulatory features and secrete trophic factors and immune receptors that regulate the microenvironment in host tissue. These specific and unique therapeutic properties make MSCs ideal as therapeutic agents in vivo. Specifically, pre-clinical and clinical investigators generated inflammatory and fibrotic diseases models, and then transplantation of MSCs into diseases models for therapeutic effects investigation. In this review, we characterize MSCs from various tissues and describe their applications for treating various inflammation and fibrotic diseases.

1. Introduction

Stem cells are characterized by two specific traits: (1) ability to self-renew and (2) varied potency to differentiate into multilineage cells [1]. Based on their origin, stem cells can be grouped into three broad categories: embryonic stem cells (ESCs), induced pluripotent stem cells (iPSCs), and adult stem cells [2,3]. ESCs and iPSCs are pluripotent stem cells. ESCs are isolated from the inner cell mass (ICM) of blastocysts [4,5]. In contrast, iPSCs are produced from adult somatic cells that are genetically reprogrammed to an ESC-like state by ectopic expression of octamer-binding transcription factor 3/4 (OCT3/4), SRY-related high-mobility group box protein-2 (SOX2), oncoprotein c-MYC, and Kruppel-like factor 4 (KLF4) [6,7]. These stem cells can differentiate into cells of the three germ layers: ectoderm, mesoderm, and endoderm. Consequently, stem cells are considered of great interest for cell therapy and regenerative medicine. However, ESCs and iPSCs exhibit immunological rejection and genetic instability, respectively. In addition, therapeutic cell transplantation of ESCs or iPSCs leads to spontaneous teratomas and tumor development [8]. Specifically, several ethical concerns still shadow the use of ESCs [9]. However, transplantation of adult stem cells circumvents the immunological rejection, genetic instability, and teratoma formation, characteristic of ESCs and iPSCs. Therefore, many researchers have investigated adult stem cells owing to their biological importance and clinical applications.
In this review, we summarized the minimal criteria for cell therapy and potential applications of adult stem cells in inflammatory and fibrotic diseases using various animal models, focusing specifically on mesenchymal stem cells (MSCs).

2. Human Mesenchymal Stem Cells (hMSCs)

2.1. Criteria for the Characterization of hMSCs for Clinical Applications

MSCs are well-known adult stem cells that have self-renewal potential and the ability to differentiate into cells of mesodermal lineage, such as chondrocytes [10,11], osteoblasts [12,13,14], and adipocytes in vitro [15,16]. Specifically, there is a need to define minimum criteria for the use of hMSC in therapy, which was declared in 2006 by the International Society for Cellular Therapy (ISCT) [17]. Three criteria were defined for hMSCs: (1) adherence to tissue culture flask when maintained in standard culture conditions; (2) over 95% of the MSC population must express specific surface antigens (CD73, CD90, and CD105), but not CD14 or CD11, CD19 or CD79α, CD34, CD45, or human leukocyte antigen-DR (HLA-DR) (under 2% positive); and (3) MSCs must differentiate into mesodermal lineage cells, such as chondrocytes, osteoblasts, or adipocytes in vitro, under standard differentiation conditions (Figure 1 and Table 1).

2.2. Isolation of hMSCs from Various Tissues

Since the first description of hMSCs isolated from bone marrow [18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34], many pre-clinical and clinical researchers isolated and characterized MSCs from various tissues, such as umbilical cord blood [24,26,35,36,37,38,39,40,41,42,43,44], adipose tissue [24,26,45,46,47,48,49,50,51,52,53,54], Wharton’s jelly [55,56,57,58,59,60,61,62], amniotic fluid [63,64,65], dental tissue [12,13,66,67,68,69,70,71,72,73,74], skin and foreskin [75,76], placenta [36,77], salivary gland [78,79], synovial fluid [80,81], synovial tissue [10,11,82,83], endometrium [84,85], limb bud [86], peripheral blood [87,88,89,90], and nasal polyps [91,92,93,94] (Figure 1 and Table 1).

3. Mesenchymal Stem Cells and Inflammatory Diseases

Inflammation is a protective response to harmful external stimuli and aids tissue repair and remodeling, however, when dysregulated can have detrimental effects [95]. In fact, excessively prolonged dysregulation of the immune system can lead to a vast array of inflammatory and autoimmune disorders, such as graft-versus-host disease (GVHD), multiple sclerosis (MS), type 1 diabetes (T1D), joint diseases, inflammatory bowel diseases (IBD), systemic lupus erythematosus (SLE), and chronic rhinosinusitis with nasal polyps (CRSwNP) [95,96]. In this chapter, we summarize what is currently known about the therapeutic effectiveness of MSCs in animal models of several immune-mediated diseases (Table 2).

3.1. Graft-Versus-Host Disease (GVHD)

GVHD is a major complication that occurs after transplantation, and is the result of donor-derived immune cells mounting an alloreactive response against host tissues and organs [97]. GVHD animal models are generated by depleting endogenous hematopoietic cells by radiation or chemotherapy, followed by the reconstitution of the immune system based on allogeneic bone marrow transplantation [98].
Miyashima investigated the transplantation of MRL/lpr mouse bone marrow-derived MSCs into irradiated recipients, leading to a GVHD-like wasting disease, but irradiated recipient animals survived much longer when the bone marrow transfer was accompanied by a bone graft [99]. In an MHC-mismatched model, in which C3H/He mice-derived MSCs were transplanted into irradiated BALB/c mice, the infusion of bone marrow-derived MSCs into the bone marrow allowed recipient mice to survive much longer than those receiving only bone marrow cells [100]. These results showed that immortalized MSC lines could suppress GVHD in this model as well [101]. T cell-derived interferon-gamma (IFN-γ) is an important factor; MSCs treated with IFN-γ prior to infusion are superior to untreated MSCs for increasing survival after bone marrow transplantation [133]. When recipients received transplantation with IFNγ-deficient T cells, MSCs were unable to enhance survival. Moreover, treatment of MSCs with IFN-γ prior to infusion enhanced the immunosuppressive capacity of MSCs; thus, IFNγ-treated MSCs suppressed GVHD even when far fewer cells had been administrated [134]. It is suggested that activation-induced production of cytokines may be required for maximal immunosuppression of MSCs in vivo [133].

3.2. Multiple Sclerosis (MS)

MS is a central nervous system (CNS) disorder, characterized by progressive demyelination of the nerves from the spinal cord and brain [135]. Most frequently, the MS animal model is experimental autoimmune encephalomyelitis (EAE), a model of induced CNS inflammation [115,116].
Most studies have shown that MSC-based therapy in EAE has potent immunosuppressive effects. Bone marrow-derived MSCs transplanted to mice showed a significantly milder disease course than untreated animals in a progressive EAE model [117]. Moreover, specifically bone marrow- and adipose tissue-derived MSCs, effectively suppressed EAE in a relapsing and remitting model [118,136,137,138].
A reduction in the secretion of inflammatory cytokines by T cells accompanies a decrease in disease activity, and T cells in MSC-transplanted mice appear to be hyporesponsive to antigenic stimulation or anergic [117,118,139]. Murine MSCs were shown to mediate immune suppression, at least in part, by a novel pathway inhibiting chemokine (C–C motif) ligand 2 (CCL2; monocyte chemoattractant protein 1, MCP1) [139]. MSCs secrete several matrix metalloproteinases (MMPs), which can cleave MSC-derived CCL2. Consequently, this inhibits, rather than activates, C–C chemokine receptor type 2 (CCR2)-expressing immune cells [140]. Moreover, MSCs derived from ongoing sick donors are unable to suppress disease upon transplantation to autologous recipients; thus, a defect in MSC function may play an important role in the pathogenesis of EAE [117].

3.3. Type 1 Diabetes (T1D)

Diabetes mellitus is classified into two types: type 1 diabetes (T1D) and type 2 diabetes (T2D). Specifically, T1D is characterized by an immune-mediated response against insulin-producing pancreatic β-cells [102]. T1D animal models are generated by the iterative treatment of streptozotocin (STZ) and damaged β-cells. This damage attracts immune cells, which leads to insulitis, and eventually to immune-mediated β-cell destruction. In the STZ-induced mouse model, syngeneic bone marrow-derived MSCs reverted hyperglycemic animals to normal blood glucose levels [103]. Autologous bone marrow-derived MSC transplantation led to increased insulin secretion and sustained normoglycemia, with a shift in T cell cytokine production toward that of TH2 cells in an STZ-induced T1D rat model [107]. MSC transplantation homed to the pancreatic and kidney islets, promoted tissue repair, and increased insulin production and renal function in STZ-treated mice [103,108].
Transplantation of MSCs with islet allografts significantly enhanced the long-term survival of STZ-induced diabetes models in rats and mice [104,109]. In a non-human primate model, allogeneic bone marrow-derived MSC and intraportal islet transplantation significantly enhanced islet engraftment and function, which was associated with an increased number of regulatory T cells [105]. In addition, MSC transplantation led to a decrease in TH1-associated cytokines and an increase in interleukin 10 (IL-10)-producing regulatory T cells in rats [109]. However, mouse-derived MSCs mediate their immunosuppressive effects by the production of metalloproteinases that cleave the alpha chain of the IL-2 receptor (CD25) from the surface of activated T cells, thus leaving T cells hyporesponsive to IL-2 [104].
The non-obese diabetic (NOD) mouse strain is an animal model for spontaneous autoimmune diabetes, and this disease animal model appears to share many features of T1D in humans. Transplantation of MSCs to NOD mice has been shown to protect them before disease onset and even cure it when administered after the onset of hyperglycemia [106,141,142]. NOD mouse-derived MSCs were unable to suppress the disease in recipients, but BALB/c mouse- or NOD-resistant mouse-derived MSCs were able to suppress disease; thus, transplantation of MSCs into NOD mice may have a defect in their ability to suppress immune responses [141]. In addition, MSC treatment was associated with a reduction in the frequency of inflammatory CD4+ T cells and an increase in the frequency of regulatory T cells [106,141,142]. These results demonstrate that MSC-based therapy suppresses the autoimmune attack of endogenous β-cells and improves the maintenance of allogeneic islet allografts in T1D animal models.

3.4. Joint Diseases: Osteoarthritis (OA) and Rheumatoid Arthritis (RA)

OA is the most common joint disease that is generated by the gradual deterioration of the cartilage in joints. Specifically, OA is defined by cartilage degradation progression, subchondral bone remodeling, bone marrow lesions, meniscal damage and synovitis [143,144]. This disease subsequently induces an immune response with further damage to the joint [145]. However, MSCs are playing immunoregulatory and suppress all immune cells, thus MSCs transplantation inhibits OA progression and differentiates into chondrocytes. In cell-to-cell contact (juxtacrine) and production of trophic soluble factors (paracrine) manner, MSCs are inhibited production and migration of tumor necrosis factor-alpha (TNF-α), production and activation of IFN-γ, and activation and proliferation of B cells, however, activated production of IL-4 and IL-10, and proliferation of T regulatory (T reg) cells [144]. Furthermore, in paracrine mechanisms, MSCs may modulate the function of immune cells in a cell-to-cell contact-dependent manner [144,146]. Interestingly, MSCs have been demonstrated to promote tissue regeneration and immunosuppression in OA animal models, and clinical trials have been registered for OA in humans [110,111,112,147]. Several preclinical studies investigated that intra-articular injection of autologous MSCs from expanded in vitro effectively reduced cartilage degradation and joints inflammation in various animals [113,114]. Intra-articular transplanted MSCs successfully engraft in the injured site of cartilage and promote its regeneration and repair [148]. Specifically, MSCs transplantation into damaged intra-articular showed benefic effects, such as reduced cartilage degeneration, attenuated joint inflammation, improved clinical and radiographic symptoms and signs of OA [144].
Rheumatoid arthritis (RA) is a common autoimmune disease characterized by chronic joint inflammation. This disease is initiated when autoreactive T cells infiltrate the synovial tissue and secrete cytokines and chemokines into the joint [119]. However, several studies demonstrated that MSCs can regulate the immune system, and control inflammation. Thus, these mechanisms are inhibited function and proliferation of T and B cells, triggered the development of CD4+CD25+FoxP3+ T reg cells, and suppressed the maturation of dendritic cells [120,149]
An animal model of RA is the collagen-induced arthritis (CIA) model [121]. Intraperitoneal injection of allogeneic bone marrow-derived MSCs at the time of initial immunization significantly decreased the incidence of disease and showed a therapeutic effect in the CIA mouse model, such as diminished count of granulocyte-macrophage colony-stimulating factor-expression CD4+ T cells, the critical ells in the pathogenesis of RA [122,123,150]. In addition, transplantation of various doses of MSCs inhibited the signs of joint inflammation and the overall joints were mildly regenerated as compared with non-transplanted animals [124,125,151,152]. Furthermore, several studies have evidenced the immunomodulatory properties of MSCs in inflammatory arthritis via suppression of T-cell proliferation as well as the function of T reg cells [122,126,151]. Moreover, MSCs suppressed the potential of follicular helper T cells in contributing to B cells [127]. These evidence indicated that MSCs have the potential to control inflammation and might be helpful in ameliorating clinical symptoms of OA and RA patients.

3.5. Inflammatory Bowel Diseases (IBD)

IBD are characterized by destructive inflammation of the colon or small intestine in humans. An animal model of IBD can be generated by treatment with dextran sulfate sodium (DSS) added to drinking water, which causes chemical damage to the intestine, or by intrarectal administration of trinitrobenzene sulfonic acid (TNBS) [153]. MSC transplantation has suppressed most measurable disease outcomes and improved survival rate in IBD animal models, specifically, DSS-induced acute colitis models [154]. In addition, transplantation of MSCs has shown therapeutic effects following intrarectal administration of TNBS [155]. Interestingly, human bone marrow, gingiva, or umbilical cord blood-derived MSC transplantation were shown to suppress experimental colitis in a DSS-induced colitis mouse model [156,157,158,159].
Several studies have demonstrated that MSC infusion increased the frequency of regulatory T cells accompanied by a reduction in the number of T cells secreting inflammatory cytokines [154,155,160]. Fas ligand (FasL)-deficient mice-derived MSCs were not able to suppress disease in DSS-induced colitis models [159,160]. MSC transplantation in colitis models can induce FasL-mediated apoptosis in T cells, and this increase in the frequency of apoptotic cells indirectly leads to an increase in regulatory T cell number; thus, macrophages engulfing apoptotic T cells increase their production of TGFβ. Furthermore, the loss of Fas in MSCs disrupted the production of CCL2, suggesting that non-apoptotic Fas signaling is required for CCL2 secretion in MSCs. Therefore, Fas-deficient MSCs are incapable of attracting T cells in close proximity to FasL-mediated killing [160].

3.6. Systemic Lupus Erythematosus (SLE)

SLE is a complex autoimmune disease that causes progressive and profound damage to a variety of organs and tissues [161]. SLE animal models were generated by the progeny of a breeding pair consisting of a New Zealand Black (NZB) mouse and New Zealand White (NZW) mouse, or mutation in the gene encoding Fas (lpr) on the MRL strain background [162]. Hybrid mice (NZB/NZW F1) developed anti-nuclear and anti-DNA antibodies along with glomerulonephritis, as seen in patients with SLE. In MRL/lpr mice, the immune cells cannot undergo Fas-mediated apoptosis, favoring pronounced lymphoproliferative disorder that leads to the development of anti-nuclear antibodies and subsequent glomerulonephritis [162].
In the NZB/NZW F1 models, the results are ambiguous. However, human umbilical cord blood-derived MSCs had only a moderate effect on disease parameters and animal survival, despite markedly reducing serum levels of pro-inflammatory cytokines, such as IL-2, TNF-α, and IL-12, and increasing anti-inflammatory cytokine levels [163]. The infusion of allogeneic bone marrow-derived MSCs reduced serum levels of anti-DNA antibodies and improved the renal function in MRL/lpr models [164]. Human bone marrow or umbilical cord blood-derived MSCs suppressed disease and led to a reduction in anti-dsDNA antibodies, proteinuria, and renal pathology in the MRL/lpr models [165,166]. Furthermore, clinical improvement was accompanied by an increase in the frequency of regulatory T cells and a reduction in the number of IL-17 producing CD4+ T cells [164].

3.7. Chronic Rhinosinusitis with Nasal Polyp (CRSwNP)

Chronic rhinosinusitis (CRS) is one of the most common chronic inflammatory diseases of the sinonasal mucosa, and is characterized by an edematous mass of hyperplastic epithelium and lamina propria prolapse of the nose, leading to nasal obstruction, hypersecretion, loss of the sense of smell, and reduced quality of life [165]. CRS is a heterogeneous disease and is generally classified into two subtypes, CRS without nasal polyps (CRSsNP) and CRS with nasal polyps (CRSwNP), which have distinct inflammatory and remodeling profiles [166,167,168,169]. Moreover, CRSwNP can be further classified into two subtypes: eosinophilic CRSwNP (E-CRSwNP) and non-eosinophilic (or neutrophilic) CRSwNP (NE-CRSwNP) [170,171]. CRSwNP animal models were generated by administration of ovalbumin (OVA) and Staphylococcus aureus enterotoxin B (SEB) for E-CRSwNP or lipopolysaccharide (LPS) for NE-CRSwNP [128,129,130,131,132]. Nasal polyps (NPs) are unique abnormal lesions that grow from the lining of the nasal and paranasal sinuses by an innate response to exogenous proteases from allergens, such as pollen, mite, fungi, and microorganisms, and type 2 inflammation plays a critical role in NP development in patients [130]. Thus, NP tissues consist of various inflammatory cells, including B cells, natural killer (NK) cells, monocytes, dendritic cells, and Th lymphocytes. Specifically, type 2 cytokines, IL-4, IL-5 and IL-13, play important roles mediating inflammation in NP development, when inducing the epithelial-derived cytokines, such as IL-25, IL-33 and thymic stromal lymphopoietin (TSLP) that drive the activation of group 2 innate lymphoid cells (ILC2s) to release type 2 cytokines in an antigen-independent manner [32].
NP-derived cell culture with MSCs showed a significant decrease in the frequency of inflammatory cells and an increase in the frequency of Treg cells. Furthermore, MSCs inhibited the proliferation of CD4+ and CD8+ T cells and changed the global cytokine profile from a pro-inflammatory to an anti-inflammatory profile, as suggested by the increase in IL-10 and decrease in IL-2, TNF-α, and IFN-γ levels [49]. However, immune modulation of MSCs on CRSwNP are still unknown in pre-clinical and clinical studies.

4. Mesenchymal Stem Cells and Fibrotic Diseases

Fibrosis is characterized by excessive accumulation of extracellular matrix components and the development of fibrous connective tissue. Consequently, fibrosis induces disruption of tissue function in the affected organs, such as the lung, liver, pancreas, and heart. In this chapter, we summarize what is currently known about the therapeutic effectiveness of MSCs against fibrotic diseases (Table 3).

4.1. Lung Fibrosis

There is a number of lung fibrotic disease animal models for the five major pathologies defined, including bronchopulmonary dysplasia (BPD), acute respiratory distress syndrome (ARDS), chronic lower respiratory disease (CLRD), cystic fibrosis (CF), and idiopathic pulmonary fibrosis (IPF) [186,187,188,189,190]. To assess the therapeutic effect, MSCs have been transplanted into lung disease models via intravenous (IV), intratracheal (IT), intraperitoneal (IP), intranasal (IN) delivery, and bone marrow transplantation (BMT), and the following effects were observed: reduction of inflammation, fibrosis and pulmonary hypertension, an increase of survival rate and extracellular matrix production, protection of alveoli, and improved pulmonary functions [172,173,190,191,192,193]. The therapeutic effects of MSCs in lung disease have been demonstrated to act via a direct bystander paracrine mechanism and through differentiation of transplanted MSCs into the pulmonary epithelium. Several studies have shown that MSCs secrete various growth factors, such as hepatocyte growth factor (HGF), epithelial growth factor (EGF), keratinocyte growth factor (KGF), vascular endothelial growth factor (VEGF), insulin growth factor (IGF), angiopoietin-1, and adiponectin [174,175,176,177,178,179,194]. Moreover, occasional in vitro alveolar epithelium differentiated MSCs transplanted into an alveolar type-II phenotype with a minor contribution to epithelium repair [192,195].

4.2. Liver Fibrosis

Cirrhosis is the end stage of progressive fibrosis caused by nonalcoholic steatohepatitis (NASH), alcohol, and viral hepatitis. This disease will progress to hepatocyte loss and subsequent disruption of the hepatic vasculature. Liver transplantation is the most effective therapy for hepatic disease. However, this strategy is hindered by the lack of donor organs, high cost, and long-term treatment with immunosuppressants after transplantation. Thus, the therapeutic potential of MSCs has been investigated as well as their differentiation capacity, immunoregulatory properties, and secretion of trophic factors.
Several studies have demonstrated that MSCs are able to differentiate into hepatic cells and recover liver function by hepatic stellate cell apoptosis and decreasing the expression of transforming growth factor (TGF)-β and alpha-smooth muscle actin (α-SMA) [196,197,198]. Furthermore, hepatic differentiation of MSCs has been demonstrated in vivo, and various trophic and immunomodulatory factors play a key therapeutic role in the treatment of liver fibrosis. Trophic factors, including antiapoptotic factors, HGF and IGF, angiogenetic factor, VEGF, mitogenic factors, EGF, HGF, nerve growth factor (NGF), and TGF-α, are secreted from MSCs and prevent the apoptosis of hepatocytes [199,200]. Moreover, the transplantation of MSCs to patients with liver fibrosis showed clinical efficiency. The results seem to be a significant improvement in the model for end-stage liver disease (MELD) score and metabolic parameters [201,202,203,204,205].

4.3. Pancreatic Fibrosis

Pancreatic fibrosis is characterized by a constant histopathological feature of chronic pancreatitis of varying etiologies, and thus, many therapeutic studies have investigated the transplantation of MSCs for treating pancreatitis. Pancreatitis is characterized by the release of pancreatic digestive enzymes from damaged exocrine cells. Specifically, chronic pancreatitis leads to damage in both the endocrine and exocrine pancreatic tissues and can be triggered by risk factors, such as alcohol consumption, genetic mutations, and pancreatic duct obstruction.
A chronic pancreatitis animal model was generated by intravenous injection of dibutyltin dichloride via the penile vein in Sprague Dawley (SD) rats [180,181,206]. Transplantation of MSCs to chronic pancreatitis animal models showed reduced pancreatic damage and decreased fibrosis [180,181,206]. This effect was considered a result of the inhibition of pancreatic satellite cells. Moreover, transplanted MSCs engrafted damaged pancreatic tissue and lowered the expression of monocyte chemoattractant protein 1 (MCP-1) vascular cell adhesion molecule 1 (VCAM-1), IL-6, and TNF-α [181]. Nuclear factor kappa B (NF-κB), an important regulator of the inflammatory response and apoptosis, was inactivated in MSCs using the inhibitor IκBαM. When IκBαM gene-modified MSCs, IκBαM-MSCs, transplanted into animal models, reduced the levels of proinflammatory cytokines, such as IL-1, IL-6, IL-8, FN, TIMP-1, TIMP-2, TNF-α, CTGF, ICAM-1, and TGF-β1, but increased anti-inflammatory cytokines, such as IL-10, and promoted the apoptosis of pancreatic stellate cells [180].

4.4. Heart Fibrosis

Heart disease involves pathological myocardial remodeling characterized by excessive deposition of extracellular matrix proteins and cardiac fibrosis. Cardiac fibrosis is caused by multiple pathways, such as hormonal, mechanical, and inflammatory mechanisms [182]. Specifically, in the inflammatory response, fibroblasts proliferate in the heart and differentiate into myofibroblasts. Additionally, myofibroblast and cardiomyocyte interactions contribute to the adverse structural and functional abnormalities observed in heart disease, including aortic stenosis.
Many studies have shown that MSCs secrete various paracrine factors, such as HGF, VEGF, IL-6, migration-related chemokine stromal cell-derived factor (SDF)-1α, and brain-derived neurotrophic factor (BDNF), and modulate several key cell processes, such as protection and/or repair under different pathological conditions [183,184,185,207,208,209,210,211,212]. Interestingly, allogeneic MSC therapy improves the endothelial function in patients with heart disease since allogeneic MSCs secrete higher levels of nitric oxide and have reduced levels of circulating VEGF compared to autologous MSCs [208]. MSCs also stimulate the survival and proliferation of adult cardiomyocytes via Akt-mediated pathways, and consequently, MSCs promote endogenous cardiomyocyte regeneration [183,209,210]. Secreted SDF-1 from MSCs induces migration, proliferation, and cardiomyocyte differentiation [183,184,211]. These results indicated that persistent activation of SDF-1 with gene therapy may be less preferable than transient, cell-based approaches for the treatment of heart failure [212]. Moreover, MSCs can degrade the extracellular matrix and promote the reduction of fibrosis in scarred tissues [213]. Transplantation of MSCs to type I collagen present in fibrotic tissue upregulates dysregulation of myocyte regeneration and repair, but downregulates growth and inflammatory gene expression, resulting in decreased MSC-induced myoblast proliferation [214,215,216,217,218,219,220,221].

5. Conclusion

MSCs have been extensively used in regenerative medicine, as they are easy to isolate from various tissues and retain their ability to expand for long periods without losing their characteristics for applications in laboratory-based scientific and pre-clinical investigations. Moreover, these cells are able to differentiate into cells of the mesodermal lineage, secrete trophic factors related to immune regulation, and migrate toward sites of inflammation and/or damaged tissue. Therefore, MSCs have significant potential in regenerative medicine and more than 200 clinical trials aimed at treating a broad range of degenerative medicines [222]. This review summarized that many pre-clinical and clinical investigators focus on the production and secretion of immunomodulatory and cytoprotective trophic factors, thus they generated various animal models of inflammatory and fibrotic diseases, and then transplanted MSCs directly or indirectly into injured tissues. After MSCs transplantation, MSCs secreted various paracrine factors, and then provided protective microenvironmental effects, and accelerated the activation of local tissue-resident progenitor populations. These secreted paracrine factors from MSCs also provided protective microenvironmental effects and accelerated the activation of local tissue-resident progenitor populations. These properties indicate that MSCs will play an important role as therapeutic agents in vivo, especially for regenerating damaged or diseased cells. However, MSCs do not always show a positive role in various inflammatory and fibrotic diseases, because MSCs can induce tumorogenesis and immunogenesis in transplanted regions. Furthermore, MSCs can move other tissue from transplantation regions because they have homing properties. Therefore, the pre-clinical and clinical investigator must conduct tumorgenesis, immunogenesis, and distribution of transplanted MSCs in other tissues using humanized animals. Moreover, in order to use MSCs therapy, MSCs isolation and cultivation must be carried out at standardized good manufacturing practice (GMP) facilities, and cultivated MSCs must be tested for purity, potency, genetic stability and various microbial tests that include mycoplasma. For applications of these MSCs to humans, MSCs should be managed and used through applications and approval by the food and drug administration of each government.

Author Contributions

J.-S.R. and E.-J.J.: conceptualization, literature search, writing, reviewing and editing; J.-Y.K., S.J.P., C.-H.K. and J.-S.K.: reviewing and editing; W.S.J.: literature search; Y.-K.C.: conceptualization, reviewing and editing. All authors have read and agreed to the published version of the manuscript.

Funding

This review was supported by the National Research Foundation of Korea (NRF) grant funded by the Korean government (MSIT) (No. 2019R1F1A1058107), and the Next Generation BioGreen 21 program (System and Synthetic Agrobiotech Center, PJ01342101), Republic of Korea.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Wei, X.; Yang, X.; Han, Z.P.; Qu, F.F.; Shao, L.; Shi, Y.F. Mesenchymal stem cells: A new trend for cell therapy. Acta Pharm. Sin. 2013, 34, 747–754. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  2. Bongso, A.; Richards, M. History and perspective of stem cell research. Best Pr. Res. Clin. Obs. Gynaecol. 2004, 18, 827–842. [Google Scholar] [CrossRef] [PubMed]
  3. Ilic, D.; Polak, J.M. Stem cells in regenerative medicine: Introduction. Br. Med. Bull. 2011, 98, 117–126. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  4. Evans, M.J.; Kaufman, M.H. Establishment in culture of pluripotential cells from mouse embryos. Nature 1981, 292, 154–156. [Google Scholar] [CrossRef]
  5. Thomson, J.A.; Itskovitz-Eldor, J.; Shapiro, S.S.; Waknitz, M.A.; Swiergiel, J.J.; Marshall, V.S.; Jones, J.M. Embryonic stem cell lines derived from human blastocysts. Science 1998, 282, 1145–1147. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  6. Takahashi, K.; Yamanaka, S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 2006, 126, 663–676. [Google Scholar] [CrossRef] [Green Version]
  7. Takahashi, K.; Tanabe, K.; Ohnuki, M.; Narita, M.; Ichisaka, T.; Tomoda, K.; Yamanaka, S. Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 2007, 131, 861–872. [Google Scholar] [CrossRef] [Green Version]
  8. Cunningham, J.J.; Ulbright, T.M.; Pera, M.F.; Looijenga, L.H. Lessons from human teratomas to guide development of safe stem cell therapies. Nat. Biotechnol. 2012, 30, 849–857. [Google Scholar] [CrossRef]
  9. Zarzeczny, A.; Caulfield, T. Emerging ethical, legal and social issues associated with stem cell research & and the current role of the moral status of the embryo. Stem Cell Rev. Rep. 2009, 5, 96–101. [Google Scholar]
  10. Ryu, J.S.; Seo, S.Y.; Jeong, E.J.; Kim, J.Y.; Koh, Y.G.; Kim, Y.I.; Choo, Y.K. Ganglioside GM3 up-regulate chondrogenic differentiation by transform growth factor receptors. Int. J. Mol. Sci. 2020, 21, 1967. [Google Scholar] [CrossRef] [Green Version]
  11. Kim, Y.I.; Ryu, J.S.; Yeo, J.E.; Choi, Y.J.; Kim, Y.S.; Ko, K.; Koh, Y.G. Overexpression of TGF-beta1 enhances chondrogenic differentiation and proliferation of human synovium-derived stem cells. Biochem. Biophys. Res. Commun. 2014, 450, 1593–1599. [Google Scholar] [CrossRef]
  12. Yang, H.J.; Jung, K.Y.; Kwak, D.H.; Lee, S.H.; Ryu, J.S.; Kim, J.S.; Chang, K.T.; Lee, J.W.; Choo, Y.K. Inhibition of ganglioside GD1a synthesis suppresses the differentiation of human mesenchymal stem cells into osteoblasts. Dev. Growth Differ. 2011, 53, 323–332. [Google Scholar] [CrossRef]
  13. Lee, S.H.; Ryu, J.S.; Lee, J.W.; Kwak, D.H.; Ko, K.; Choo, Y.K. Comparison of ganglioside expression between human adipose-and dental pulp-derived stem cell differentiation into osteoblasts. Arch. Pharm. Res. 2010, 33, 585–591. [Google Scholar] [CrossRef]
  14. Kim, S.M.; Jung, J.U.; Ryu, J.S.; Jin, J.W.; Yang, H.J.; Ko, K.; You, H.K.; Jung, K.Y.; Choo, Y.K. Effects of gangliosides on the differentiation of human mesenchymal stem cells into osteoblasts by modulating epidermal growth factor receptors. Biochem. Biophys. Res. Commun. 2008, 371, 866–871. [Google Scholar] [CrossRef]
  15. Qu, P.; Wang, L.; Min, Y.; McKennett, L.; Keller, J.R.; Lin, P.C. Vav1 regulates mesenchymal stem cell differentiation decision between adipocyte and chondrocyte via Sirt1. Stem Cells 2016, 34, 1934–1946. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  16. Kanda, Y.; Hinata, T.; Kang, S.W.; Watanabe, Y. Reactive oxygen species mediate adipocyte differentiation in mesenchymal stem cells. Life Sci. 2011, 89, 250–258. [Google Scholar] [CrossRef] [PubMed]
  17. Dominici, M.; Le Blanc, K.; Mueller, I.; Slaper-Cortenbach, I.; Marini, F.; Krause, D.; Deans, R.; Keating, A.; Prockop, D.; Horwitz, E. Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy 2006, 8, 315–317. [Google Scholar] [CrossRef]
  18. Pittenger, M.F.; Mackay, A.M.; Beck, S.C.; Jaiswal, R.K.; Douglas, R.; Mosca, J.D.; Moorman, M.A.; Simonetti, D.W.; Craig, S.; Marshak, D.R. Multilineage potential of adult human mesenchymal stem cells. Science 1999, 284, 143–147. [Google Scholar] [CrossRef] [Green Version]
  19. Pezato, R.; de Almeida, D.C.; Bezerra, T.F.; Silva, F.D.S.; Perez-Novo, C.; Gregorio, L.C.; Voegels, R.L.; Camara, N.O.; Bachert, C. Immunoregulatory effects of bone marrow-derived mesenchymal stem cells in the nasal polyp microenvironment. Mediat. Inflamm. 2014, 2014, 583409. [Google Scholar] [CrossRef] [Green Version]
  20. Mamidi, M.K.; Nathan, K.G.; Singh, G.; Thrichelvam, S.T.; Mohd Yusof, N.A.; Fakharuzi, N.A.; Zakaria, Z.; Bhonde, R.; Das, A.K.; Majumdar, A.S. Comparative cellular and molecular analyses of pooled bone marrow multipotent mesenchymal stromal cells during continuous passaging and after successive cryopreservation. J. Cell. Biochem. 2012, 113, 3153–3164. [Google Scholar] [CrossRef]
  21. Otsuru, S.; Hofmann, T.J.; Olson, T.S.; Dominici, M.; Horwitz, E.M. Improved isolation and expansion of bone marrow mesenchymal stromal cells using a novel marrow filter device. Cytotherapy 2013, 15, 146–153. [Google Scholar] [CrossRef] [PubMed]
  22. Gronthos, S.; Graves, S.E.; Ohta, S.; Simmons, P.J. The STRO-1+ fraction of adult human bone marrow contains the osteogenic precursors. Blood 1994, 84, 4164–4173. [Google Scholar] [CrossRef] [Green Version]
  23. Stewart, K.; Walsh, S.; Screen, J.; Jefferiss, C.M.; Chainey, J.; Jordan, G.R.; Beresford, J.N. Further characterization of cells expressing STRO-1 in cultures of adult human bone marrow stromal cells. J. Bone. Min. Res. 1999, 14, 1345–1356. [Google Scholar] [CrossRef]
  24. Wagner, W.; Wein, F.; Seckinger, A.; Frankhauser, M.; Wirkner, U.; Krause, U.; Blake, J.; Schwager, C.; Eckstein, V.; Ansorge, W.; et al. Comparative characteristics of mesenchymal stem cells from human bone marrow, adipose tissue, and umbilical cord blood. Exp. Hematol. 2005, 33, 1402–1416. [Google Scholar] [CrossRef]
  25. Ranera, B.; Remacha, A.R.; Alvarez-Arguedas, S.; Castiella, T.; Vazquez, F.J.; Romero, A.; Zaragoza, P.; Martin-Burriel, I.; Rodellar, C. Expansion under hypoxic conditions enhances the chondrogenic potential of equine bone marrow-derived mesenchymal stem cells. Vet. J. 2013, 195, 248–251. [Google Scholar] [CrossRef] [PubMed]
  26. Zhang, X.; Hirai, M.; Cantero, S.; Ciubotariu, R.; Dobrila, L.; Hirsh, A.; Igura, K.; Satoh, H.; Yokomi, I.; Nishimura, T.; et al. Isolation and characterization of mesenchymal stem cells from human umbilical cord blood: Reevaluation of critical factors for successful isolation and high ability to proliferate and differentiate to chondrocytes as compared to mesenchymal stem cells from bone marrow and adipose tissue. J. Cell. Biochem. 2011, 112, 1206–1218. [Google Scholar]
  27. Muruganandan, S.; Roman, A.A.; Sinal, C.J. Adipocyte differentiation of bone marrow-derived mesenchymal stem cells: Cross talk with the osteoblastogenic program. Cell. Mol. Life Sci. 2009, 66, 236–253. [Google Scholar] [CrossRef]
  28. Stock, P.; Bruckner, S.; Winkler, S.; Dollinger, M.M.; Christ, B. Human bone marrow mesenchymal stem cell-derived hepatocytes improve the mouse liver after acute acetaminophen intoxication by preventing progress of injury. Int. J. Mol. Sci. 2014, 15, 7004–7028. [Google Scholar] [CrossRef] [Green Version]
  29. Xu, W.; Zhang, X.; Qian, H.; Zhu, W.; Sun, X.; Hu, J.; Zhou, H.; Chen, Y. Mesenchymal stem cells from adult human bone marrow differentiate into a cardiomyocyte phenotype in vitro. Exp. Biol. Med. (Maywood) 2004, 229, 623–631. [Google Scholar] [CrossRef]
  30. Tang, D.Q.; Wang, Q.; Burkhardt, B.R.; Litherland, S.A.; Atkinson, M.A.; Yang, L.J. In vitro generation of functional insulin-producing cells from human bone marrow-derived stem cells, but long-term culture running risk of malignant transformation. Am. J. Stem Cells 2012, 1, 114–127. [Google Scholar]
  31. Gabr, M.M.; Zakaria, M.M.; Refaie, A.F.; Ismail, A.M.; Abou-El-Mahasen, M.A.; Ashamallah, S.A.; Khater, S.M.; El-Halawani, S.M.; Ibrahim, R.Y.; Uin, G.S.; et al. Insulin-producing cells from adult human bone marrow mesenchymal stem cells control streptozotocin-induced diabetes in nude mice. Cell Transpl. 2013, 22, 133–145. [Google Scholar] [CrossRef] [Green Version]
  32. Phadnis, S.M.; Joglekar, M.V.; Dalvi, M.P.; Muthyala, S.; Nair, P.D.; Ghaskadbi, S.M.; Bhonde, R.R.; Hardikar, A.A. Human bone marrow-derived mesenchymal cells differentiate and mature into endocrine pancreatic lineage in vivo. Cytotherapy 2011, 13, 279–293. [Google Scholar] [CrossRef]
  33. Barzilay, R.; Ben-Zur, T.; Bulvik, S.; Melamed, E.; Offen, D. Lentiviral delivery of LMX1a enhances dopaminergic phenotype in differentiated human bone marrow mesenchymal stem cells. Stem Cells Dev. 2009, 18, 591–601. [Google Scholar] [CrossRef]
  34. Wilkins, A.; Kemp, K.; Ginty, M.; Hares, K.; Mallam, E.; Scolding, N. Human bone marrow-derived mesenchymal stem cells secrete brain-derived neurotrophic factor which promotes neuronal survival in vitro. Stem Cell Res. 2009, 3, 63–70. [Google Scholar] [CrossRef] [Green Version]
  35. Bieback, K.; Kern, S.; Kluter, H.; Eichler, H. Critical parameters for the isolation of mesenchymal stem cells from umbilical cord blood. Stem Cells 2004, 22, 625–634. [Google Scholar] [CrossRef] [Green Version]
  36. Miao, Z.; Jin, J.; Chen, L.; Zhu, J.; Huang, W.; Zhao, J.; Qian, H.; Zhang, X. Isolation of mesenchymal stem cells from human placenta: Comparison with human bone marrow mesenchymal stem cells. Cell Biol. Int. 2006, 30, 681–687. [Google Scholar] [CrossRef]
  37. La Rocca, G.; Anzalone, R.; Corrao, S.; Magno, F.; Loria, T.; Lo Iacono, M.; Di Stefano, A.; Giannuzzi, P.; Marasa, L.; Cappello, F.; et al. Isolation and characterization of Oct-4+/HLA-G+ mesenchymal stem cells from human umbilical cord matrix: Differentiation potential and detection of new markers. Histochem. Cell Biol. 2009, 131, 267–282. [Google Scholar] [CrossRef]
  38. Kita, K.; Gauglitz, G.G.; Phan, T.T.; Herndon, D.N.; Jeschke, M.G. Isolation and characterization of mesenchymal stem cells from the sub-amniotic human umbilical cord lining membrane. Stem Cells Dev. 2010, 19, 491–502. [Google Scholar] [CrossRef]
  39. Moretti, P.; Hatlapatka, T.; Marten, D.; Lavrentieva, A.; Majore, I.; Hass, R.; Kasper, C. Mesenchymal stromal cells derived from human umbilical cord tissues: Primitive cells with potential for clinical and tissue engineering applications. Adv. Biochem. Eng. Biotechnol. 2010, 123, 29–54. [Google Scholar]
  40. Majore, I.; Moretti, P.; Stahl, F.; Hass, R.; Kasper, C. Growth and differentiation properties of mesenchymal stromal cell populations derived from whole human umbilical cord. Stem Cell Rev. Rep. 2011, 7, 17–31. [Google Scholar] [CrossRef]
  41. Hang, H.; Yu, Y.; Wu, N.; Huang, Q.; Xia, Q.; Bian, J. Induction of highly functional hepatocytes from human umbilical cord mesenchymal stem cells by HNF4alpha transduction. PLoS ONE 2014, 9, e104133. [Google Scholar] [CrossRef]
  42. An, S.Y.; Han, J.; Lim, H.J.; Park, S.Y.; Kim, J.H.; Do, B.R.; Kim, J.H. Valproic acid promotes differentiation of hepatocyte-like cells from whole human umbilical cord-derived mesenchymal stem cells. Tissue Cell 2014, 46, 127–135. [Google Scholar] [CrossRef]
  43. Prabakar, K.R.; Dominguez-Bendala, J.; Molano, R.D.; Pileggi, A.; Villate, S.; Ricordi, C.; Inverardi, L. Generation of glucose-responsive, insulin-producing cells from human umbilical cord blood-derived mesenchymal stem cells. Cell Transpl. 2012, 21, 1321–1339. [Google Scholar] [CrossRef] [Green Version]
  44. Zhao, F.; Qu, Y.; Liu, H.; Du, B.; Mu, D. Umbilical cord blood mesenchymal stem cells co-modified by TERT and BDNF: A novel neuroprotective therapy for neonatal hypoxic-ischemic brain damage. Int. J. Dev. Neurosci. 2014, 38, 147–154. [Google Scholar] [CrossRef] [Green Version]
  45. Pendleton, C.; Li, Q.; Chesler, D.A.; Yuan, K.; Guerrero-Cazares, H.; Quinones-Hinojosa, A. Mesenchymal stem cells derived from adipose tissue vs. bone marrow: In vitro comparison of their tropism towards gliomas. PLoS ONE 2013, 8, e58198. [Google Scholar] [CrossRef]
  46. Baglioni, S.; Francalanci, M.; Squecco, R.; Lombardi, A.; Cantini, G.; Angeli, R.; Gelmini, S.; Guasti, D.; Benvenuti, S.; Annunziato, F.; et al. Characterization of human adult stem-cell populations isolated from visceral and subcutaneous adipose tissue. FASEB J. 2009, 23, 3494–3505. [Google Scholar] [CrossRef]
  47. Gronthos, S.; Franklin, D.M.; Leddy, H.A.; Robey, P.G.; Storms, R.W.; Gimble, J.M. Surface protein characterization of human adipose tissue-derived stromal cells. J. Cell. Physiol. 2001, 189, 54–63. [Google Scholar] [CrossRef]
  48. Kim, Y.S.; Choi, Y.J.; Suh, D.S.; Heo, D.B.; Kim, Y.I.; Ryu, J.S.; Koh, Y.G. Mesenchymal stem cell implantation in osteoarthritic knees: Is fibrin glue effective as a scaffold? Am. J. Sports Med. 2015, 43, 176–185. [Google Scholar] [CrossRef]
  49. Cho, K.S.; Kim, Y.W.; Kang, M.J.; Park, H.Y.; Hong, S.L.; Roh, H.J. Immunomodulatory effect of mesenchymal stem cells on T lymphocyte and cytokine expression in nasal polyps. Otolaryngol. Head Neck Surg. 2014, 150, 1062–1070. [Google Scholar] [CrossRef]
  50. Wang, Y.; Wang, F.; Zhao, H.; Zhang, X.; Chen, H.; Zhang, K. Human adipose-derived mesenchymal stem cells are resistant to HBV infection during differentiation into hepatocytes in vitro. Int. J. Mol. Sci. 2014, 15, 6096–6110. [Google Scholar] [CrossRef] [Green Version]
  51. Choi, Y.S.; Dusting, G.J.; Stubbs, S.; Arunothayaraj, S.; Han, X.L.; Collas, P.; Morrison, W.A.; Dilley, R.J. Differentiation of human adipose-derived stem cells into beating cardiomyocytes. J. Cell. Mol. Med. 2010, 14, 878–889. [Google Scholar] [CrossRef] [Green Version]
  52. Timper, K.; Seboek, D.; Eberhardt, M.; Linscheid, P.; Christ-Crain, M.; Keller, U.; Muller, B.; Zulewski, H. Human adipose tissue-derived mesenchymal stem cells differentiate into insulin, somatostatin, and glucagon expressing cells. Biochem. Biophys. Res. Commun. 2006, 341, 1135–1140. [Google Scholar] [CrossRef]
  53. Safford, K.M.; Hicok, K.C.; Safford, S.D.; Halvorsen, Y.D.; Wilkison, W.O.; Gimble, J.M.; Rice, H.E. Neurogenic differentiation of murine and human adipose-derived stromal cells. Biochem. Biophys. Res. Commun. 2002, 294, 371–379. [Google Scholar] [CrossRef]
  54. Kang, S.K.; Lee, D.H.; Bae, Y.C.; Kim, H.K.; Baik, S.Y.; Jung, J.S. Improvement of neurological deficits by intracerebral transplantation of human adipose tissue-derived stromal cells after cerebral ischemia in rats. Exp. Neurol. 2003, 183, 355–366. [Google Scholar] [CrossRef]
  55. Kuznetsov, S.A.; Krebsbach, P.H.; Satomura, K.; Kerr, J.; Riminucci, M.; Benayahu, D.; Robey, P.G. Single-colony derived strains of human marrow stromal fibroblasts form bone after transplantation in vivo. J. Bone Min. Res. 1997, 12, 1335–1347. [Google Scholar] [CrossRef]
  56. Hou, T.; Xu, J.; Wu, X.; Xie, Z.; Luo, F.; Zhang, Z.; Zeng, L. Umbilical cord Wharton’s Jelly: A new potential cell source of mesenchymal stromal cells for bone tissue engineering. Tissue Eng. Part A 2009, 15, 2325–2334. [Google Scholar] [CrossRef]
  57. Salehinejad, P.; Alitheen, N.B.; Ali, A.M.; Omar, A.R.; Mohit, M.; Janzamin, E.; Samani, F.S.; Torshizi, Z.; Nematollahi-Mahani, S.N. Comparison of different methods for the isolation of mesenchymal stem cells from human umbilical cord Wharton’s Jelly. In Vitro Cell. Dev. Biol. Anim. 2012, 48, 75–83. [Google Scholar] [CrossRef]
  58. Christodoulou, I.; Kolisis, F.N.; Papaevangeliou, D.; Zoumpourlis, V. Comparative evaluation of human mesenchymal stem cells of fetal (Wharton’s Jelly) and adult (Adipose Tissue) origin during prolonged in vitro expansion: Considerations for cytotherapy. Stem Cells Int. 2013, 2013, 246134. [Google Scholar] [CrossRef] [Green Version]
  59. Yoon, J.H.; Roh, E.Y.; Shin, S.; Jung, N.H.; Song, E.Y.; Chang, J.Y.; Kim, B.J.; Jeon, H.W. Comparison of explant-derived and enzymatic digestion-derived MSCs and the growth factors from Wharton’s Jelly. Biomed. Res. Int. 2013, 2013, 428726. [Google Scholar] [CrossRef] [Green Version]
  60. Wang, H.S.; Hung, S.C.; Peng, S.T.; Huang, C.C.; Wei, H.M.; Guo, Y.J.; Fu, Y.S.; Lai, M.C.; Chen, C.C. Mesenchymal stem cells in the Wharton’s Jelly of the human umbilical cord. Stem Cells 2004, 22, 1330–1337. [Google Scholar] [CrossRef] [Green Version]
  61. Anzalone, R.; Lo Iacono, M.; Corrao, S.; Magno, F.; Loria, T.; Cappello, F.; Zummo, G.; Farina, F.; La Rocca, G. New emerging potentials for human Wharton’s Jelly mesenchymal stem cells: Immunological features and hepatocyte-like differentiative capacity. Stem Cells Dev. 2010, 19, 423–438. [Google Scholar] [CrossRef]
  62. Datta, I.; Mishra, S.; Mohanty, L.; Pulikkot, S.; Joshi, P.G. Neuronal plasticity of human Wharton’s Jelly mesenchymal stromal cells to the dopaminergic cell type compared with human bone marrow mesenchymal stromal cells. Cytotherapy 2011, 13, 918–932. [Google Scholar] [CrossRef]
  63. Int Anker, P.S.; Scherjon, S.A.; Kleijburg-van der Keur, C.; Noort, W.A.; Claas, F.H.; Willemze, R.; Fibbe, W.E.; Kanhai, H.H. Amniotic fluid as a novel source of mesenchymal stem cells for therapeutic transplantation. Blood 2003, 102, 1548–1549. [Google Scholar] [CrossRef]
  64. Tsai, M.S.; Lee, J.L.; Chang, Y.J.; Hwang, S.M. Isolation of human multipotent mesenchymal stem cells from second-trimester amniotic fluid using a novel two-stage culture protocol. Hum. Reprod. 2004, 19, 1450–1456. [Google Scholar] [CrossRef]
  65. Cai, J.; Li, W.; Su, H.; Qin, D.; Yang, J.; Zhu, F.; Xu, J.; He, W.; Guo, X.; Labuda, K.; et al. Generation of human induced pluripotent stem cells from umbilical cord matrix and amniotic membrane mesenchymal cells. J. Biol. Chem. 2010, 285, 11227–11234. [Google Scholar] [CrossRef] [Green Version]
  66. Huang, G.T.; Gronthos, S.; Shi, S. Mesenchymal stem cells derived from dental tissues vs. those from other sources: Their biology and role in regenerative medicine. J. Dent. Res. 2009, 88, 792–806. [Google Scholar] [CrossRef]
  67. Hilkens, P.; Gervois, P.; Fanton, Y.; Vanormelingen, J.; Martens, W.; Struys, T.; Politis, C.; Lambrichts, I.; Bronckaers, A. Effect of isolation methodology on stem cell properties and multilineage differentiation potential of human dental pulp stem cells. Cell Tissue Res. 2013, 353, 65–78. [Google Scholar] [CrossRef]
  68. Seifrtova, M.; Havelek, R.; Cmielova, J.; Jiroutova, A.; Soukup, T.; Bruckova, L.; Mokry, J.; English, D.; Rezacova, M. The response of human ectomesenchymal dental pulp stem cells to cisplatin treatment. Int. Endod. J. 2012, 45, 401–412. [Google Scholar] [CrossRef]
  69. Kadar, K.; Kiraly, M.; Porcsalmy, B.; Molnar, B.; Racz, G.Z.; Blazsek, J.; Kallo, K.; Szabo, E.L.; Gera, I.; Gerber, G.; et al. Differentiation potential of stem cells from human dental origin—Promise for tissue engineering. J. Physiol. Pharm. 2009, 60 (Suppl. 7), 167–175. [Google Scholar]
  70. Ryu, J.S.; Ko, K.; Lee, J.W.; Park, S.B.; Byun, S.J.; Jeong, E.J.; Ko, K.; Choo, Y.K. Gangliosides are involved in neural differentiation of human dental pulp-derived stem cells. Biochem. Biophys. Res. Commun. 2009, 387, 266–271. [Google Scholar] [CrossRef]
  71. Govindasamy, V.; Ronald, V.S.; Abdullah, A.N.; Nathan, K.R.; Ab Aziz, Z.A.; Abdullah, M.; Musa, S.; Kasim, N.H.; Bhonde, R.R. Differentiation of dental pulp stem cells into islet-like aggregates. J. Dent. Res. 2011, 90, 646–652. [Google Scholar] [CrossRef] [Green Version]
  72. Kanafi, M.M.; Rajeshwari, Y.B.; Gupta, S.; Dadheech, N.; Nair, P.D.; Gupta, P.K.; Bhonde, R.R. Transplantation of islet-like cell clusters derived from human dental pulp stem cells restores normoglycemia in diabetic mice. Cytotherapy 2013, 15, 1228–1236. [Google Scholar] [CrossRef]
  73. Vollner, F.; Ernst, W.; Driemel, O.; Morsczeck, C. A two-step strategy for neuronal differentiation in vitro of human dental follicle cells. Differentiation 2009, 77, 433–441. [Google Scholar] [CrossRef] [Green Version]
  74. Wang, J.; Wang, X.; Sun, Z.; Wang, X.; Yang, H.; Shi, S.; Wang, S. Stem cells from human-exfoliated deciduous teeth can differentiate into dopaminergic neuron-like cells. Stem Cells Dev. 2010, 19, 1375–1383. [Google Scholar] [CrossRef] [PubMed]
  75. Bartsch, G.; Yoo, J.J.; De Coppi, P.; Siddiqui, M.M.; Schuch, G.; Pohl, H.G.; Fuhr, J.; Perin, L.; Soker, S.; Atala, A. Propagation, expansion, and multilineage differentiation of human somatic stem cells from dermal progenitors. Stem Cells Dev. 2005, 14, 337–348. [Google Scholar] [CrossRef]
  76. Riekstina, U.; Muceniece, R.; Cakstina, I.; Muiznieks, I.; Ancans, J. Characterization of human skin-derived mesenchymal stem cell proliferation rate in different growth conditions. Cytotechnology 2008, 58, 153–162. [Google Scholar] [CrossRef] [Green Version]
  77. Raynaud, C.M.; Maleki, M.; Lis, R.; Ahmed, B.; Al-Azwani, I.; Malek, J.; Safadi, F.F.; Rafii, A. Comprehensive characterization of mesenchymal stem cells from human placenta and fetal membrane and their response to osteoactivin stimulation. Stem Cells Int. 2012, 2012, 658356. [Google Scholar] [CrossRef]
  78. Rotter, N.; Oder, J.; Schlenke, P.; Lindner, U.; Bohrnsen, F.; Kramer, J.; Rohwedel, J.; Huss, R.; Brandau, S.; Wollenberg, B.; et al. Isolation and characterization of adult stem cells from human salivary glands. Stem Cells Dev. 2008, 17, 509–518. [Google Scholar] [CrossRef]
  79. Sato, A.; Okumura, K.; Matsumoto, S.; Hattori, K.; Hattori, S.; Shinohara, M.; Endo, F. Isolation, tissue localization, and cellular characterization of progenitors derived from adult human salivary glands. Cloning Stem Cells 2007, 9, 191–205. [Google Scholar] [CrossRef]
  80. Morito, T.; Muneta, T.; Hara, K.; Ju, Y.J.; Mochizuki, T.; Makino, H.; Umezawa, A.; Sekiya, I. Synovial fluid-derived mesenchymal stem cells increase after intra-articular ligament injury in humans. Rheumatology (Oxf.) 2008, 47, 1137–1143. [Google Scholar] [CrossRef] [Green Version]
  81. Hatakeyama, A.; Uchida, S.; Utsunomiya, H.; Tsukamoto, M.; Nakashima, H.; Nakamura, E.; Pascual-Garrido, C.; Sekiya, I.; Sakai, A. Isolation and characterization of synovial mesenchymal stem cell derived from hip joints: A comparative analysis with a matched control knee group. Stem Cells Int. 2017, 2017, 9312329. [Google Scholar] [CrossRef]
  82. Ryu, J.S.; Jung, Y.H.; Cho, M.Y.; Yeo, J.E.; Choi, Y.J.; Kim, Y.I.; Koh, Y.G. Co-culture with human synovium-derived mesenchymal stem cells inhibits inflammatory activity and increases cell proliferation of sodium nitroprusside-stimulated chondrocytes. Biochem. Biophys. Res. Commun. 2014, 447, 715–720. [Google Scholar] [CrossRef]
  83. Sakaguchi, Y.; Sekiya, I.; Yagishita, K.; Muneta, T. Comparison of human stem cells derived from various mesenchymal tissues: Superiority of synovium as a cell source. Arthritis Rheum. 2005, 52, 2521–2529. [Google Scholar] [CrossRef]
  84. Schuring, A.N.; Schulte, N.; Kelsch, R.; Ropke, A.; Kiesel, L.; Gotte, M. Characterization of endometrial mesenchymal stem-like cells obtained by endometrial biopsy during routine diagnostics. Fertil. Steril. 2011, 95, 423–426. [Google Scholar] [CrossRef]
  85. Cheng, Y.; Li, L.; Wang, D.; Guo, Q.; He, Y.; Liang, T.; Sun, L.; Wang, X.; Cheng, Y.; Zhang, G. Characteristics of human endometrium-derived mesenchymal stem cells and their tropism to endometriosis. Stem Cells Int. 2017, 2017, 4794827. [Google Scholar] [CrossRef] [Green Version]
  86. Jiao, F.; Wang, J.; Dong, Z.L.; Wu, M.J.; Zhao, T.B.; Li, D.D.; Wang, X. Human mesenchymal stem cells derived from limb bud can differentiate into all three embryonic germ layers lineages. Cell. Reprogram. 2012, 14, 324–333. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  87. Ab Kadir, R.; Zainal Ariffin, S.H.; Megat Abdul Wahab, R.; Kermani, S.; Senafi, S. Characterization of mononucleated human peripheral blood cells. Sci. World J. 2012, 2012, 843843. [Google Scholar] [CrossRef] [Green Version]
  88. Lin, W.; Xu, L.; Lin, S.; Shi, L.; Wang, B.; Pan, Q.; Lee, W.Y.W.; Li, G. Characterisation of multipotent stem cells from human peripheral blood using an improved protocol. J. Orthop. Transl. 2019, 19, 18–28. [Google Scholar] [CrossRef]
  89. Ouryazdanpanah, N.; Dabiri, S.; Derakhshani, A.; Vahidi, R.; Farsinejad, A. Peripheral blood-derived mesenchymal stem cells: Growth factor-free isolation, molecular characterization and differentiation. Iran J. Pathol. 2018, 13, 461–466. [Google Scholar] [PubMed]
  90. Li, S.; Huang, K.J.; Wu, J.C.; Hu, M.S.; Sanyal, M.; Hu, M.; Longaker, M.T.; Lorenz, H.P. Peripheral blood-derived mesenchymal stem cells: Candidate cells responsible for healing critical-sized calvarial bone defects. Stem Cells Transl. Med. 2015, 4, 359–368. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  91. Cho, J.S.; Park, J.H.; Kang, J.H.; Kim, S.E.; Park, I.H.; Lee, H.M. Isolation and characterization of multipotent mesenchymal stem cells in nasal polyps. Exp. Biol. Med. (Maywood) 2015, 240, 185–193. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  92. De Oliveira, P.W.; Pezato, R.; Agudelo, J.S.; Perez-Novo, C.A.; Berghe, W.V.; Camara, N.O.; de Almeida, D.C.; Gregorio, L.C. Nasal polyp-derived mesenchymal stromal cells exhibit lack of immune-associated molecules and high levels of stem/progenitor cells markers. Front. Immunol. 2017, 8, 39. [Google Scholar] [CrossRef]
  93. Shafiee, A.; Kabiri, M.; Ahmadbeigi, N.; Yazdani, S.O.; Mojtahed, M.; Amanpour, S.; Soleimani, M. Nasal septum-derived multipotent progenitors: A potent source for stem cell-based regenerative medicine. Stem Cells Dev. 2011, 20, 2077–2091. [Google Scholar] [CrossRef] [Green Version]
  94. Koennecke, M.; Boscke, R.; Pfannerstill, A.C.; Reers, S.; Elsner, M.; Fell, B.; Richter, A.; Bruchhage, K.L.; Schumann, S.; Pries, R.; et al. Neuronal differentiation capability of nasal polyps of chronic rhinosinusitis. Arch. Immunol. Exp. (Warsz) 2017, 65, 431–443. [Google Scholar] [CrossRef]
  95. Okin, D.; Medzhitov, R. Evolution of inflammatory diseases. Curr. Biol. 2012, 22, R733–R740. [Google Scholar] [CrossRef] [Green Version]
  96. Davidson, A.; Diamond, B. Autoimmune diseases. N. Engl. J. Med. 2001, 345, 340–350. [Google Scholar] [CrossRef]
  97. Socie, G.; Ritz, J. Current issues in chronic graft-versus-host disease. Blood 2014, 124, 374–384. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  98. Schroeder, M.A.; DiPersio, J.F. Mouse models of graft-versus-host disease: Advances and limitations. Dis. Model. Mech. 2011, 4, 318–333. [Google Scholar] [CrossRef] [Green Version]
  99. Miyashima, S.; Nagata, N.; Nakagawa, T.; Hosaka, N.; Takeuchi, K.; Ogawa, R.; Ikehara, S. Prevention of lpr-graft-versus-host disease and transfer of autoimmune diseases in normal C57BL/6 mice by transplantation of bone marrow cells plus bones (stromal cells) from MRL/lpr mice. J. Immunol. 1996, 156, 79–84. [Google Scholar]
  100. Chung, N.G.; Jeong, D.C.; Park, S.J.; Choi, B.O.; Cho, B.; Kim, H.K.; Chun, C.S.; Won, J.H.; Han, C.W. Cotransplantation of marrow stromal cells may prevent lethal graft-versus-host disease in major histocompatibility complex mismatched murine hematopoietic stem cell transplantation. Int. J. Hematol. 2004, 80, 370–376. [Google Scholar] [CrossRef]
  101. Joo, S.Y.; Cho, K.A.; Jung, Y.J.; Kim, H.S.; Park, S.Y.; Choi, Y.B.; Hong, K.M.; Woo, S.Y.; Seoh, J.Y.; Cho, S.J.; et al. Mesenchymal stromal cells inhibit graft-versus-host disease of mice in a dose-dependent manner. Cytotherapy 2010, 12, 361–370. [Google Scholar] [CrossRef]
  102. Van Belle, T.L.; Coppieters, K.T.; von Herrath, M.G. Type 1 diabetes: Etiology, immunology, and therapeutic strategies. Physiol. Rev. 2011, 91, 79–118. [Google Scholar] [CrossRef] [PubMed]
  103. Ezquer, F.E.; Ezquer, M.E.; Parrau, D.B.; Carpio, D.; Yanez, A.J.; Conget, P.A. Systemic administration of multipotent mesenchymal stromal cells reverts hyperglycemia and prevents nephropathy in type 1 diabetic mice. Biol. Blood Marrow Transpl. 2008, 14, 631–640. [Google Scholar] [CrossRef] [Green Version]
  104. Ding, Y.; Xu, D.; Feng, G.; Bushell, A.; Muschel, R.J.; Wood, K.J. Mesenchymal stem cells prevent the rejection of fully allogenic islet grafts by the immunosuppressive activity of matrix metalloproteinase-2 and -9. Diabetes 2009, 58, 1797–1806. [Google Scholar] [CrossRef] [Green Version]
  105. Berman, D.M.; Willman, M.A.; Han, D.; Kleiner, G.; Kenyon, N.M.; Cabrera, O.; Karl, J.A.; Wiseman, R.W.; O’Connor, D.H.; Bartholomew, A.M.; et al. Mesenchymal stem cells enhance allogeneic islet engraftment in nonhuman primates. Diabetes 2010, 59, 2558–2568. [Google Scholar] [CrossRef] [Green Version]
  106. Madec, A.M.; Mallone, R.; Afonso, G.; Abou Mrad, E.; Mesnier, A.; Eljaafari, A.; Thivolet, C. Mesenchymal stem cells protect NOD mice from diabetes by inducing regulatory T cells. Diabetologia 2009, 52, 1391–1399. [Google Scholar] [CrossRef] [Green Version]
  107. Boumaza, I.; Srinivasan, S.; Witt, W.T.; Feghali-Bostwick, C.; Dai, Y.; Garcia-Ocana, A.; Feili-Hariri, M. Autologous bone marrow-derived rat mesenchymal stem cells promote PDX-1 and insulin expression in the islets, alter T cell cytokine pattern and preserve regulatory T cells in the periphery and induce sustained normoglycemia. J. Autoimmun. 2009, 32, 33–42. [Google Scholar] [CrossRef] [PubMed]
  108. Lee, R.H.; Seo, M.J.; Reger, R.L.; Spees, J.L.; Pulin, A.A.; Olson, S.D.; Prockop, D.J. Multipotent stromal cells from human marrow home to and promote repair of pancreatic islets and renal glomeruli in diabetic NOD/scid mice. Proc. Natl. Acad. Sci. USA 2006, 103, 17438–17443. [Google Scholar] [CrossRef] [Green Version]
  109. Solari, M.G.; Srinivasan, S.; Boumaza, I.; Unadkat, J.; Harb, G.; Garcia-Ocana, A.; Feili-Hariri, M. Marginal mass islet transplantation with autologous mesenchymal stem cells promotes long-term islet allograft survival and sustained normoglycemia. J. Autoimmun. 2009, 32, 116–124. [Google Scholar] [CrossRef]
  110. Sato, M.; Uchida, K.; Nakajima, H.; Miyazaki, T.; Guerrero, A.R.; Watanabe, S.; Roberts, S.; Baba, H. Direct transplantation of mesenchymal stem cells into the knee joints of Hartley strain guinea pigs with spontaneous osteoarthritis. Arthritis Res. Ther. 2012, 14, 1–9. [Google Scholar] [CrossRef] [Green Version]
  111. Toghraie, F.; Razmkhah, M.; Gholipour, M.A.; Faghih, Z.; Chenari, N.; Torabi Nezhad, S.; Nazhvani Dehghani, S.; Ghaderi, A. Scaffold-free adipose-derived stem cells (ASCs) improve experimentally induced osteoarthritis in rabbits. Arch. Iran. Med. 2012, 15, 495–499. [Google Scholar]
  112. Soler, R.; Orozco, L.; Munar, A.; Huguet, M.; Lopez, R.; Vives, J.; Coll, R.; Codinach, M.; Garcia-Lopez, J. Final results of a phase I-II trial using ex vivo expanded autologous Mesenchymal Stromal Cells for the treatment of osteoarthritis of the knee confirming safety and suggesting cartilage regeneration. Knee 2016, 23, 647–654. [Google Scholar] [CrossRef] [PubMed]
  113. Kim, J.E.; Lee, S.M.; Kim, S.H.; Tatman, P.; Gee, A.O.; Kim, D.H.; Lee, K.E.; Jung, Y.; Kim, S.J. Effect of self-assembled peptide-mesenchymal stem cell complex on the progression of osteoarthritis in a rat model. Int. J. Nanomed. 2014, 9 (Suppl. 1), 141–157. [Google Scholar] [CrossRef] [Green Version]
  114. Li, M.; Luo, X.; Lv, X.; Liu, V.; Zhao, G.; Zhang, X.; Cao, W.; Wang, R.; Wang, W. In vivo human adipose-derived mesenchymal stem cell tracking after intra-articular delivery in a rat osteoarthritis model. Stem Cell Res. Ther. 2016, 7, 160. [Google Scholar] [CrossRef] [Green Version]
  115. Rao, P.; Segal, B.M. Experimental autoimmune encephalomyelitis. Methods Mol. Biol. 2012, 900, 363–380. [Google Scholar]
  116. Constantinescu, C.S.; Farooqi, N.; O’Brien, K.; Gran, B. Experimental autoimmune encephalomyelitis (EAE) as a model for multiple sclerosis (MS). Br. J. Pharm. 2011, 164, 1079–1106. [Google Scholar] [CrossRef]
  117. Zappia, E.; Casazza, S.; Pedemonte, E.; Benvenuto, F.; Bonanni, I.; Gerdoni, E.; Giunti, D.; Ceravolo, A.; Cazzanti, F.; Frassoni, F.; et al. Mesenchymal stem cells ameliorate experimental autoimmune encephalomyelitis inducing T-cell anergy. Blood 2005, 106, 1755–1761. [Google Scholar] [CrossRef] [Green Version]
  118. Gerdoni, E.; Gallo, B.; Casazza, S.; Musio, S.; Bonanni, I.; Pedemonte, E.; Mantegazza, R.; Frassoni, F.; Mancardi, G.; Pedotti, R.; et al. Mesenchymal stem cells effectively modulate pathogenic immune response in experimental autoimmune encephalomyelitis. Ann. Neurol. 2007, 61, 219–227. [Google Scholar] [CrossRef]
  119. Holmdahl, R.; Malmstrom, V.; Burkhardt, H. Autoimmune priming, tissue attack and chronic inflammation—The three stages of rheumatoid arthritis. Eur. J. Immunol. 2014, 44, 1593–1599. [Google Scholar] [CrossRef]
  120. Abbasi, M.; Mousavi, M.J.; Jamalzehi, S.; Alimohammadi, R.; Bezvan, M.H.; Mohammadi, H.; Aslani, S. Strategies toward rheumatoid arthritis therapy; the old and the new. J. Cell. Physiol. 2019, 234, 10018–10031. [Google Scholar] [CrossRef]
  121. Brand, D.D.; Latham, K.A.; Rosloniec, E.F. Collagen-induced arthritis. Nat. Protoc. 2007, 2, 1269–1275. [Google Scholar] [CrossRef]
  122. Augello, A.; Tasso, R.; Negrini, S.M.; Cancedda, R.; Pennesi, G. Cell therapy using allogeneic bone marrow mesenchymal stem cells prevents tissue damage in collagen-induced arthritis. Arthritis Rheum. 2007, 56, 1175–1186. [Google Scholar] [CrossRef] [PubMed]
  123. Lopez-Santalla, M.; Mancheno-Corvo, P.; Menta, R.; Lopez-Belmonte, J.; DelaRosa, O.; Bueren, J.A.; Dalemans, W.; Lombardo, E.; Garin, M.I. Human adipose-derived mesenchymal stem cells modulate experimental autoimmune arthritis by modifying early adaptive T cell responses. Stem Cells 2015, 33, 3493–3503. [Google Scholar] [CrossRef]
  124. Liu, Y.; Mu, R.; Wang, S.; Long, L.; Liu, X.; Li, R.; Sun, J.; Guo, J.; Zhang, X.; Guo, J.; et al. Therapeutic potential of human umbilical cord mesenchymal stem cells in the treatment of rheumatoid arthritis. Arthritis Res. Ther. 2010, 12, R210. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  125. Kehoe, O.; Cartwright, A.; Askari, A.; El Haj, A.J.; Middleton, J. Intra-articular injection of mesenchymal stem cells leads to reduced inflammation and cartilage damage in murine antigen-induced arthritis. J. Transl. Med. 2014, 12, 157. [Google Scholar] [CrossRef] [Green Version]
  126. Gonzalez-Rey, E.; Gonzalez, M.A.; Varela, N.; O’Valle, F.; Hernandez-Cortes, P.; Rico, L.; Buscher, D.; Delgado, M. Human adipose-derived mesenchymal stem cells reduce inflammatory and T cell responses and induce regulatory T cells in vitro in rheumatoid arthritis. Ann. Rheum. Dis. 2010, 69, 241–248. [Google Scholar] [CrossRef] [Green Version]
  127. Liu, R.; Li, X.; Zhang, Z.; Zhou, M.; Sun, Y.; Su, D.; Feng, X.; Gao, X.; Shi, S.; Chen, W.; et al. Allogeneic mesenchymal stem cells inhibited T follicular helper cell generation in rheumatoid arthritis. Sci. Rep. 2015, 5, 12777. [Google Scholar] [CrossRef] [Green Version]
  128. Grgic, M.V.; Cupic, H.; Kalogjera, L.; Baudoin, T. Surgical treatment for nasal polyposis: Predictors of outcome. Eur. Arch. Otorhinolaryngol. 2015, 272, 3735–3743. [Google Scholar] [CrossRef]
  129. Sreeparvathi, A.; Kalyanikuttyamma, L.K.; Kumar, M.; Sreekumar, N.; Veerasigamani, N. Significance of blood eosinophil count in patients with chronic rhinosinusitis with nasal polyposis. J. Clin. Diagn. Res. 2017, 11, MC08–MC11. [Google Scholar] [CrossRef]
  130. Kim, D.Y.; Lee, S.H.; Carter, R.G.; Kato, A.; Schleimer, R.P.; Cho, S.H. A recently established murine model of nasal polyps demonstrates activation of B cells, as occurs in human nasal polyps. Am. J. Respir. Cell Mol. Biol. 2016, 55, 170–175. [Google Scholar] [CrossRef] [Green Version]
  131. Wang, S.; Zhang, H.; Xi, Z.; Huang, J.; Nie, J.; Zhou, B.; Deng, Y.; Tao, Z. Establishment of a mouse model of lipopolysaccharide-induced neutrophilic nasal polyps. Exp. Ther. Med. 2017, 14, 5275–5282. [Google Scholar] [CrossRef]
  132. Takabayashi, T.; Schleimer, R.P. Formation of nasal polyps: The roles of innate type 2 inflammation and deposition of fibrin. J. Allergy Clin. Immunol. 2020, 145, 740–750. [Google Scholar] [CrossRef] [Green Version]
  133. Polchert, D.; Sobinsky, J.; Douglas, G.; Kidd, M.; Moadsiri, A.; Reina, E.; Genrich, K.; Mehrotra, S.; Setty, S.; Smith, B.; et al. IFN-gamma activation of mesenchymal stem cells for treatment and prevention of graft versus host disease. Eur. J. Immunol. 2008, 38, 1745–1755. [Google Scholar] [CrossRef] [Green Version]
  134. Tobin, L.M.; Healy, M.E.; English, K.; Mahon, B.P. Human mesenchymal stem cells suppress donor CD4(+) T cell proliferation and reduce pathology in a humanized mouse model of acute graft-versus-host disease. Clin. Exp. Immunol. 2013, 172, 333–348. [Google Scholar] [CrossRef]
  135. Nylander, A.; Hafler, D.A. Multiple sclerosis. J. Clin. Investig. 2012, 122, 1180–1188. [Google Scholar] [CrossRef]
  136. Rafei, M.; Birman, E.; Forner, K.; Galipeau, J. Allogeneic mesenchymal stem cells for treatment of experimental autoimmune encephalomyelitis. Mol. Ther. 2009, 17, 1799–1803. [Google Scholar] [CrossRef]
  137. Bai, L.; Lennon, D.P.; Eaton, V.; Maier, K.; Caplan, A.I.; Miller, S.D.; Miller, R.H. Human bone marrow-derived mesenchymal stem cells induce Th2-polarized immune response and promote endogenous repair in animal models of multiple sclerosis. Glia 2009, 57, 1192–1203. [Google Scholar] [CrossRef] [Green Version]
  138. Gordon, D.; Pavlovska, G.; Glover, C.P.; Uney, J.B.; Wraith, D.; Scolding, N.J. Human mesenchymal stem cells abrogate experimental allergic encephalomyelitis after intraperitoneal injection, and with sparse CNS infiltration. Neurosci. Lett. 2008, 448, 71–73. [Google Scholar] [CrossRef] [Green Version]
  139. Rafei, M.; Campeau, P.M.; Aguilar-Mahecha, A.; Buchanan, M.; Williams, P.; Birman, E.; Yuan, S.; Young, Y.K.; Boivin, M.N.; Forner, K.; et al. Mesenchymal stromal cells ameliorate experimental autoimmune encephalomyelitis by inhibiting CD4 Th17 T cells in a CC chemokine ligand 2-dependent manner. J. Immunol. 2009, 182, 5994–6002. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  140. Rafei, M.; Hsieh, J.; Fortier, S.; Li, M.; Yuan, S.; Birman, E.; Forner, K.; Boivin, M.N.; Doody, K.; Tremblay, M.; et al. Mesenchymal stromal cell-derived CCL2 suppresses plasma cell immunoglobulin production via STAT3 inactivation and PAX5 induction. Blood 2008, 112, 4991–4998. [Google Scholar] [CrossRef]
  141. Fiorina, P.; Jurewicz, M.; Augello, A.; Vergani, A.; Dada, S.; La Rosa, S.; Selig, M.; Godwin, J.; Law, K.; Placidi, C.; et al. Immunomodulatory function of bone marrow-derived mesenchymal stem cells in experimental autoimmune type 1 diabetes. J. Immunol. 2009, 183, 993–1004. [Google Scholar] [CrossRef] [Green Version]
  142. Bassi, E.J.; Moraes-Vieira, P.M.; Moreira-Sa, C.S.; Almeida, D.C.; Vieira, L.M.; Cunha, C.S.; Hiyane, M.I.; Basso, A.S.; Pacheco-Silva, A.; Camara, N.O. Immune regulatory properties of allogeneic adipose-derived mesenchymal stem cells in the treatment of experimental autoimmune diabetes. Diabetes 2012, 61, 2534–2545. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  143. Goldring, M.B. Articular cartilage degradation in osteoarthritis. HSS J. 2012, 8, 7–9. [Google Scholar] [CrossRef] [Green Version]
  144. Harrell, C.R.; Markovic, B.S.; Fellabaum, C.; Arsenijevic, A.; Volarevic, V. Mesenchymal stem cell-based therapy of osteoarthritis: Current knowledge and future perspectives. Biomed. Pharm. 2019, 109, 2318–2326. [Google Scholar] [CrossRef]
  145. Benito, M.J.; Veale, D.J.; FitzGerald, O.; van den Berg, W.B.; Bresnihan, B. Synovial tissue inflammation in early and late osteoarthritis. Ann. Rheum. Dis. 2005, 64, 1263–1267. [Google Scholar] [CrossRef] [Green Version]
  146. Volarevic, V.; Al-Qahtani, A.; Arsenijevic, N.; Pajovic, S.; Lukic, M.L. Interleukin-1 receptor antagonist (IL-1Ra) and IL-1Ra producing mesenchymal stem cells as modulators of diabetogenesis. Autoimmunity 2010, 43, 255–263. [Google Scholar] [CrossRef]
  147. Horie, M.; Choi, H.; Lee, R.H.; Reger, R.L.; Ylostalo, J.; Muneta, T.; Sekiya, I.; Prockop, D.J. Intra-articular injection of human mesenchymal stem cells (MSCs) promote rat meniscal regeneration by being activated to express Indian hedgehog that enhances expression of type II collagen. Osteoarthr. Cartil. 2012, 20, 1197–1207. [Google Scholar] [CrossRef] [Green Version]
  148. Mokbel, A.N.; El Tookhy, O.S.; Shamaa, A.A.; Rashed, L.A.; Sabry, D.; El Sayed, A.M. Homing and reparative effect of intra-articular injection of autologus mesenchymal stem cells in osteoarthritic animal model. BMC Musculoskelet. Disord. 2011, 12, 259. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  149. Uccelli, A.; de Rosbo, N.K. The immunomodulatory function of mesenchymal stem cells: Mode of action and pathways. Ann. N. Y. Acad. Sci. 2015, 1351, 114–126. [Google Scholar] [CrossRef]
  150. Cornish, A.L.; Campbell, I.K.; McKenzie, B.S.; Chatfield, S.; Wicks, I.P. G-CSF and GM-CSF as therapeutic targets in rheumatoid arthritis. Nat. Rev. Rheumatol. 2009, 5, 554–559. [Google Scholar] [CrossRef]
  151. Gonzalez, M.A.; Gonzalez-Rey, E.; Rico, L.; Buscher, D.; Delgado, M. Treatment of experimental arthritis by inducing immune tolerance with human adipose-derived mesenchymal stem cells. Arthritis Rheum. 2009, 60, 1006–1019. [Google Scholar] [CrossRef]
  152. Mao, F.; Xu, W.R.; Qian, H.; Zhu, W.; Yan, Y.M.; Shao, Q.X.; Xu, H.X. Immunosuppressive effects of mesenchymal stem cells in collagen-induced mouse arthritis. Inflamm. Res. 2010, 59, 219–225. [Google Scholar] [CrossRef]
  153. Low, D.; Nguyen, D.D.; Mizoguchi, E. Animal models of ulcerative colitis and their application in drug research. Drug Des. Devel. Ther. 2013, 7, 1341–1357. [Google Scholar]
  154. Gonzalez-Rey, E.; Anderson, P.; Gonzalez, M.A.; Rico, L.; Buscher, D.; Delgado, M. Human adult stem cells derived from adipose tissue protect against experimental colitis and sepsis. Gut 2009, 58, 929–939. [Google Scholar] [CrossRef]
  155. Gonzalez, M.A.; Gonzalez-Rey, E.; Rico, L.; Buscher, D.; Delgado, M. Adipose-derived mesenchymal stem cells alleviate experimental colitis by inhibiting inflammatory and autoimmune responses. Gastroenterology 2009, 136, 978–989. [Google Scholar] [CrossRef]
  156. Zhang, Q.; Shi, S.; Liu, Y.; Uyanne, J.; Shi, Y.; Shi, S.; Le, A.D. Mesenchymal stem cells derived from human gingiva are capable of immunomodulatory functions and ameliorate inflammation-related tissue destruction in experimental colitis. J. Immunol. 2009, 183, 7787–7798. [Google Scholar] [CrossRef] [Green Version]
  157. Kim, H.S.; Shin, T.H.; Lee, B.C.; Yu, K.R.; Seo, Y.; Lee, S.; Seo, M.S.; Hong, I.S.; Choi, S.W.; Seo, K.W.; et al. Human umbilical cord blood mesenchymal stem cells reduce colitis in mice by activating NOD2 signaling to COX2. Gastroenterology 2013, 145, 1392–1403. [Google Scholar] [CrossRef]
  158. Tanaka, F.; Tominaga, K.; Ochi, M.; Tanigawa, T.; Watanabe, T.; Fujiwara, Y.; Ohta, K.; Oshitani, N.; Higuchi, K.; Arakawa, T. Exogenous administration of mesenchymal stem cells ameliorates dextran sulfate sodium-induced colitis via anti-inflammatory action in damaged tissue in rats. Life Sci. 2008, 83, 771–779. [Google Scholar] [CrossRef]
  159. Zhao, Y.; Wang, L.; Jin, Y.; Shi, S. Fas ligand regulates the immunomodulatory properties of dental pulp stem cells. J. Dent. Res. 2012, 91, 948–954. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  160. Akiyama, K.; Chen, C.; Wang, D.; Xu, X.; Qu, C.; Yamaza, T.; Cai, T.; Chen, W.; Sun, L.; Shi, S. Mesenchymal-stem-cell-induced immunoregulation involves FAS-ligand-/FAS-mediated T cell apoptosis. Cell Stem Cell 2012, 10, 544–555. [Google Scholar] [CrossRef] [Green Version]
  161. Tsokos, G.C. Systemic lupus erythematosus. N. Engl. J. Med. 2011, 365, 2110–2121. [Google Scholar] [CrossRef] [Green Version]
  162. Peng, S.L. Experimental use of mouse models of systemic lupus erythematosus. Methods Mol. Biol. 2012, 900, 135–168. [Google Scholar]
  163. Chang, J.W.; Hung, S.P.; Wu, H.H.; Wu, W.M.; Yang, A.H.; Tsai, H.L.; Yang, L.Y.; Lee, O.K. Therapeutic effects of umbilical cord blood-derived mesenchymal stem cell transplantation in experimental lupus nephritis. Cell Transpl. 2011, 20, 245–257. [Google Scholar] [CrossRef] [PubMed]
  164. Sun, L.; Akiyama, K.; Zhang, H.; Yamaza, T.; Hou, Y.; Zhao, S.; Xu, T.; Le, A.; Shi, S. Mesenchymal stem cell transplantation reverses multiorgan dysfunction in systemic lupus erythematosus mice and humans. Stem Cells 2009, 27, 1421–1432. [Google Scholar] [CrossRef] [Green Version]
  165. Zhou, K.; Zhang, H.; Jin, O.; Feng, X.; Yao, G.; Hou, Y.; Sun, L. Transplantation of human bone marrow mesenchymal stem cell ameliorates the autoimmune pathogenesis in MRL/lpr mice. Cell. Mol. Immunol. 2008, 5, 417–424. [Google Scholar] [CrossRef] [Green Version]
  166. Gu, Z.; Akiyama, K.; Ma, X.; Zhang, H.; Feng, X.; Yao, G.; Hou, Y.; Lu, L.; Gilkeson, G.S.; Silver, R.M.; et al. Transplantation of umbilical cord mesenchymal stem cells alleviates lupus nephritis in MRL/lpr mice. Lupus 2010, 19, 1502–1514. [Google Scholar] [CrossRef] [PubMed]
  167. Pawankar, R. Nasal polyposis: An update: Editorial review. Curr. Opin. Allergy Clin. Immunol. 2003, 3, 1–6. [Google Scholar] [CrossRef]
  168. Fokkens, W.J.; Lund, V.J.; Mullol, J.; Bachert, C.; Alobid, I.; Baroody, F.; Cohen, N.; Cervin, A.; Douglas, R.; Gevaert, P.; et al. EPOS 2012: European position paper on rhinosinusitis and nasal polyps 2012. A summary for otorhinolaryngologists. Rhinology 2012, 50, 1–12. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  169. Meltzer, E.O.; Hamilos, D.L.; Hadley, J.A.; Lanza, D.C.; Marple, B.F.; Nicklas, R.A.; Bachert, C.; Baraniuk, J.; Baroody, F.M.; Benninger, M.S.; et al. Rhinosinusitis: Establishing definitions for clinical research and patient care. J. Allergy Clin. Immunol. 2004, 114, 155–212. [Google Scholar] [CrossRef] [PubMed]
  170. Cao, P.P.; Li, H.B.; Wang, B.F.; Wang, S.B.; You, X.J.; Cui, Y.H.; Wang, D.Y.; Desrosiers, M.; Liu, Z. Distinct immunopathologic characteristics of various types of chronic rhinosinusitis in adult Chinese. J. Allergy Clin. Immunol. 2009, 124, 478–484. [Google Scholar] [CrossRef]
  171. Van Crombruggen, K.; Zhang, N.; Gevaert, P.; Tomassen, P.; Bachert, C. Pathogenesis of chronic rhinosinusitis: Inflammation. J. Allergy Clin. Immunol. 2011, 128, 728–732. [Google Scholar] [CrossRef]
  172. Prota, L.F.; Lassance, R.M.; Maron-Gutierrez, T.; Castiglione, R.C.; Garcia, C.S.; Santana, M.C.; Souza-Menezes, J.; Abreu, S.C.; Samoto, V.; Santiago, M.F.; et al. Bone marrow mononuclear cell therapy led to alveolar-capillary membrane repair, improving lung mechanics in endotoxin-induced acute lung injury. Cell Transpl. 2010, 19, 965–971. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  173. Zhang, W.G.; He, L.; Shi, X.M.; Wu, S.S.; Zhang, B.; Mei, L.; Xu, Y.J.; Zhang, Z.X.; Zhao, J.P.; Zhang, H.L. Regulation of transplanted mesenchymal stem cells by the lung progenitor niche in rats with chronic obstructive pulmonary disease. Respir. Res. 2014, 15, 33. [Google Scholar] [CrossRef] [Green Version]
  174. Meng, F.; Meliton, A.; Moldobaeva, N.; Mutlu, G.; Kawasaki, Y.; Akiyama, T.; Birukova, A.A. Asef mediates HGF protective effects against LPS-induced lung injury and endothelial barrier dysfunction. Am. J. Physiol. Lung Cell. Mol. Physiol. 2015, 308, L452–L463. [Google Scholar] [CrossRef] [Green Version]
  175. Katsha, A.M.; Ohkouchi, S.; Xin, H.; Kanehira, M.; Sun, R.; Nukiwa, T.; Saijo, Y. Paracrine factors of multipotent stromal cells ameliorate lung injury in an elastase-induced emphysema model. Mol. Ther. 2011, 19, 196–203. [Google Scholar] [CrossRef] [PubMed]
  176. Lee, J.W.; Fang, X.; Gupta, N.; Serikov, V.; Matthay, M.A. Allogeneic human mesenchymal stem cells for treatment of E. coli endotoxin-induced acute lung injury in the ex vivo perfused human lung. Proc. Natl. Acad. Sci. USA 2009, 106, 16357–16362. [Google Scholar] [CrossRef] [Green Version]
  177. Thebaud, B.; Ladha, F.; Michelakis, E.D.; Sawicka, M.; Thurston, G.; Eaton, F.; Hashimoto, K.; Harry, G.; Haromy, A.; Korbutt, G.; et al. Vascular endothelial growth factor gene therapy increases survival, promotes lung angiogenesis, and prevents alveolar damage in hyperoxia-induced lung injury: Evidence that angiogenesis participates in alveolarization. Circulation 2005, 112, 2477–2486. [Google Scholar] [CrossRef] [Green Version]
  178. Mei, S.H.; McCarter, S.D.; Deng, Y.; Parker, C.H.; Liles, W.C.; Stewart, D.J. Prevention of LPS-induced acute lung injury in mice by mesenchymal stem cells overexpressing angiopoietin 1. PLoS Med. 2007, 4, e269. [Google Scholar] [CrossRef]
  179. McCarter, S.D.; Mei, S.H.; Lai, P.F.; Zhang, Q.W.; Parker, C.H.; Suen, R.S.; Hood, R.D.; Zhao, Y.D.; Deng, Y.; Han, R.N.; et al. Cell-based angiopoietin-1 gene therapy for acute lung injury. Am. J. Respir. Crit. Care Med. 2007, 175, 1014–1026. [Google Scholar] [CrossRef] [Green Version]
  180. Qin, T.; Liu, C.J.; Zhang, H.W.; Pan, Y.F.; Tang, Q.; Liu, J.K.; Wang, Y.Z.; Hu, M.X.; Xue, F. Effect of the IkBalpha mutant gene delivery to mesenchymal stem cells on rat chronic pancreatitis. Genet. Mol. Res. 2014, 13, 371–385. [Google Scholar] [CrossRef] [PubMed]
  181. Zhou, C.H.; Li, M.L.; Qin, A.L.; Lv, S.X.; Wen, T.; Zhu, X.Y.; Li, L.Y.; Dong, Y.; Hu, C.Y.; Hu, D.M.; et al. Reduction of fibrosis in dibutyltin dichloride-induced chronic pancreatitis using rat umbilical mesenchymal stem cells from Wharton’s Jelly. Pancreas 2013, 42, 1291–1302. [Google Scholar] [CrossRef]
  182. Nicoletti, A.; Michel, J.B. Cardiac fibrosis and inflammation: Interaction with hemodynamic and hormonal factors. Cardiovasc. Res. 1999, 41, 532–543. [Google Scholar] [CrossRef]
  183. Hatzistergos, K.E.; Quevedo, H.; Oskouei, B.N.; Hu, Q.; Feigenbaum, G.S.; Margitich, I.S.; Mazhari, R.; Boyle, A.J.; Zambrano, J.P.; Rodriguez, J.E.; et al. Bone marrow mesenchymal stem cells stimulate cardiac stem cell proliferation and differentiation. Circ. Res. 2010, 107, 913–922. [Google Scholar] [CrossRef] [Green Version]
  184. Hatzistergos, K.E.; Saur, D.; Seidler, B.; Balkan, W.; Breton, M.; Valasaki, K.; Takeuchi, L.M.; Landin, A.M.; Khan, A.; Hare, J.M. Stimulatory effects of mesenchymal stem cells on cKit+ cardiac stem cells are mediated by SDF1/CXCR4 and SCF/cKit signaling pathways. Circ. Res. 2016, 119, 921–930. [Google Scholar] [CrossRef] [Green Version]
  185. Quevedo, H.C.; Hatzistergos, K.E.; Oskouei, B.N.; Feigenbaum, G.S.; Rodriguez, J.E.; Valdes, D.; Pattany, P.M.; Zambrano, J.P.; Hu, Q.; McNiece, I.; et al. Allogeneic mesenchymal stem cells restore cardiac function in chronic ischemic cardiomyopathy via trilineage differentiating capacity. Proc. Natl. Acad. Sci. USA 2009, 106, 14022–14027. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  186. Asmussen, S.; Ito, H.; Traber, D.L.; Lee, J.W.; Cox, R.A.; Hawkins, H.K.; McAuley, D.F.; McKenna, D.H.; Traber, L.D.; Zhuo, H.; et al. Human mesenchymal stem cells reduce the severity of acute lung injury in a sheep model of bacterial pneumonia. Thorax 2014, 69, 819–825. [Google Scholar] [CrossRef] [Green Version]
  187. Feizpour, A.; Boskabady, M.H.; Ghorbani, A. Adipose-derived stromal cell therapy affects lung inflammation and tracheal responsiveness in guinea pig model of COPD. PLoS ONE 2014, 9, e108974. [Google Scholar] [CrossRef]
  188. Loi, R.; Beckett, T.; Goncz, K.K.; Suratt, B.T.; Weiss, D.J. Limited restoration of cystic fibrosis lung epithelium in vivo with adult bone marrow-derived cells. Am. J. Respir. Crit. Care Med. 2006, 173, 171–179. [Google Scholar] [CrossRef] [Green Version]
  189. Tanaka, K.; Fujita, T.; Umezawa, H.; Namiki, K.; Yoshioka, K.; Hagihara, M.; Sudo, T.; Kimura, S.; Tatsumi, K.; Kasuya, Y. Therapeutic effect of lung mixed culture-derived epithelial cells on lung fibrosis. Lab. Investig. 2014, 94, 1247–1259. [Google Scholar] [CrossRef]
  190. Aslam, M.; Baveja, R.; Liang, O.D.; Fernandez-Gonzalez, A.; Lee, C.; Mitsialis, S.A.; Kourembanas, S. Bone marrow stromal cells attenuate lung injury in a murine model of neonatal chronic lung disease. Am. J. Respir. Crit. Care Med. 2009, 180, 1122–1130. [Google Scholar] [CrossRef] [Green Version]
  191. Alphonse, R.S.; Vadivel, A.; Fung, M.; Shelley, W.C.; Critser, P.J.; Ionescu, L.; O’Reilly, M.; Ohls, R.K.; McConaghy, S.; Eaton, F.; et al. Existence, functional impairment, and lung repair potential of endothelial colony-forming cells in oxygen-induced arrested alveolar growth. Circulation 2014, 129, 2144–2157. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  192. Van Haaften, T.; Byrne, R.; Bonnet, S.; Rochefort, G.Y.; Akabutu, J.; Bouchentouf, M.; Rey-Parra, G.J.; Galipeau, J.; Haromy, A.; Eaton, F.; et al. Airway delivery of mesenchymal stem cells prevents arrested alveolar growth in neonatal lung injury in rats. Am. J. Respir. Crit. Care Med. 2009, 180, 1131–1142. [Google Scholar] [CrossRef] [Green Version]
  193. Zhang, X.; Wang, H.; Shi, Y.; Peng, W.; Zhang, S.; Zhang, W.; Xu, J.; Mei, Y.; Feng, Z. Role of bone marrow-derived mesenchymal stem cells in the prevention of hyperoxia-induced lung injury in newborn mice. Cell Biol. Int. 2012, 36, 589–594. [Google Scholar] [CrossRef]
  194. Ionescu, L.I.; Alphonse, R.S.; Arizmendi, N.; Morgan, B.; Abel, M.; Eaton, F.; Duszyk, M.; Vliagoftis, H.; Aprahamian, T.R.; Walsh, K.; et al. Airway delivery of soluble factors from plastic-adherent bone marrow cells prevents murine asthma. Am. J. Respir. Cell Mol. Biol. 2012, 46, 207–216. [Google Scholar] [CrossRef] [Green Version]
  195. De Paepe, M.E.; Mao, Q.; Ghanta, S.; Hovanesian, V.; Padbury, J.F. Alveolar epithelial cell therapy with human cord blood-derived hematopoietic progenitor cells. Am. J. Pathol. 2011, 178, 1329–1339. [Google Scholar] [CrossRef] [PubMed]
  196. Jang, Y.O.; Kim, M.Y.; Cho, M.Y.; Baik, S.K.; Cho, Y.Z.; Kwon, S.O. Effect of bone marrow-derived mesenchymal stem cells on hepatic fibrosis in a thioacetamide-induced cirrhotic rat model. BMC Gastroenterol. 2014, 14, 198. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  197. Schubert, T.; Xhema, D.; Veriter, S.; Schubert, M.; Behets, C.; Delloye, C.; Gianello, P.; Dufrane, D. The enhanced performance of bone allografts using osteogenic-differentiated adipose-derived mesenchymal stem cells. Biomaterials 2011, 32, 8880–8891. [Google Scholar] [CrossRef]
  198. Baksh, D.; Yao, R.; Tuan, R.S. Comparison of proliferative and multilineage differentiation potential of human mesenchymal stem cells derived from umbilical cord and bone marrow. Stem Cells 2007, 25, 1384–1392. [Google Scholar] [CrossRef] [Green Version]
  199. Mohammadi Gorji, S.; Karimpor Malekshah, A.A.; Hashemi-Soteh, M.B.; Rafiei, A.; Parivar, K.; Aghdami, N. Effect of mesenchymal stem cells on Doxorubicin-induced fibrosis. Cell J. 2012, 14, 142–151. [Google Scholar]
  200. Eom, Y.W.; Shim, K.Y.; Baik, S.K. Mesenchymal stem cell therapy for liver fibrosis. Korean J. Intern. Med. 2015, 30, 580–589. [Google Scholar] [CrossRef]
  201. Zhang, Z.; Lin, H.; Shi, M.; Xu, R.; Fu, J.; Lv, J.; Chen, L.; Lv, S.; Li, Y.; Yu, S.; et al. Human umbilical cord mesenchymal stem cells improve liver function and ascites in decompensated liver cirrhosis patients. J. Gastroenterol. Hepatol. 2012, 27 (Suppl. 2), 112–120. [Google Scholar] [CrossRef] [PubMed]
  202. Wang, L.; Li, J.; Liu, H.; Li, Y.; Fu, J.; Sun, Y.; Xu, R.; Lin, H.; Wang, S.; Lv, S.; et al. Pilot study of umbilical cord-derived mesenchymal stem cell transfusion in patients with primary biliary cirrhosis. J. Gastroenterol. Hepatol. 2013, 28 (Suppl. 1), 85–92. [Google Scholar] [CrossRef]
  203. El-Ansary, M.; Abdel-Aziz, I.; Mogawer, S.; Abdel-Hamid, S.; Hammam, O.; Teaema, S.; Wahdan, M. Phase II trial: Undifferentiated versus differentiated autologous mesenchymal stem cells transplantation in Egyptian patients with HCV induced liver cirrhosis. Stem Cell Rev. Rep. 2012, 8, 972–981. [Google Scholar] [CrossRef] [PubMed]
  204. Salama, H.; Zekri, A.R.; Medhat, E.; Al Alim, S.A.; Ahmed, O.S.; Bahnassy, A.A.; Lotfy, M.M.; Ahmed, R.; Musa, S. Peripheral vein infusion of autologous mesenchymal stem cells in Egyptian HCV-positive patients with end-stage liver disease. Stem Cell Res. Ther. 2014, 5, 70. [Google Scholar] [CrossRef] [Green Version]
  205. Xu, L.; Gong, Y.; Wang, B.; Shi, K.; Hou, Y.; Wang, L.; Lin, Z.; Han, Y.; Lu, L.; Chen, D.; et al. Randomized trial of autologous bone marrow mesenchymal stem cells transplantation for hepatitis B virus cirrhosis: Regulation of Treg/Th17 cells. J. Gastroenterol. Hepatol. 2014, 29, 1620–1628. [Google Scholar] [CrossRef]
  206. Kawakubo, K.; Ohnishi, S.; Fujita, H.; Kuwatani, M.; Onishi, R.; Masamune, A.; Takeda, H.; Sakamoto, N. Effect of fetal membrane-derived mesenchymal stem cell transplantation in rats with acute and chronic pancreatitis. Pancreas 2016, 45, 707–713. [Google Scholar] [CrossRef] [Green Version]
  207. Cao, Y.; Sun, Z.; Liao, L.; Meng, Y.; Han, Q.; Zhao, R.C. Human adipose tissue-derived stem cells differentiate into endothelial cells in vitro and improve postnatal neovascularization in vivo. Biochem. Biophys. Res. Commun. 2005, 332, 370–379. [Google Scholar] [CrossRef]
  208. Premer, C.; Blum, A.; Bellio, M.A.; Schulman, I.H.; Hurwitz, B.E.; Parker, M.; Dermarkarian, C.R.; DiFede, D.L.; Balkan, W.; Khan, A.; et al. Allogeneic mesenchymal stem cells restore endothelial function in heart failure by stimulating endothelial progenitor cells. EBioMedicine 2015, 2, 467–475. [Google Scholar] [CrossRef] [Green Version]
  209. Beigi, F.; Schmeckpeper, J.; Pow-Anpongkul, P.; Payne, J.A.; Zhang, L.; Zhang, Z.; Huang, J.; Mirotsou, M.; Dzau, V.J. C3orf58, a novel paracrine protein, stimulates cardiomyocyte cell-cycle progression through the PI3K-AKT-CDK7 pathway. Circ. Res. 2013, 113, 372–380. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  210. Mirotsou, M.; Zhang, Z.; Deb, A.; Zhang, L.; Gnecchi, M.; Noiseux, N.; Mu, H.; Pachori, A.; Dzau, V. Secreted frizzled related protein 2 (Sfrp2) is the key Akt-mesenchymal stem cell-released paracrine factor mediating myocardial survival and repair. Proc. Natl. Acad. Sci. USA 2007, 104, 1643–1648. [Google Scholar] [CrossRef] [Green Version]
  211. Suzuki, G.; Iyer, V.; Lee, T.C.; Canty, J.M., Jr. Autologous mesenchymal stem cells mobilize cKit+ and CD133+ bone marrow progenitor cells and improve regional function in hibernating myocardium. Circ. Res. 2011, 109, 1044–1054. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  212. Chung, E.S.; Miller, L.; Patel, A.N.; Anderson, R.D.; Mendelsohn, F.O.; Traverse, J.; Silver, K.H.; Shin, J.; Ewald, G.; Farr, M.J.; et al. Changes in ventricular remodelling and clinical status during the year following a single administration of stromal cell-derived factor-1 non-viral gene therapy in chronic ischaemic heart failure patients: The STOP-HF randomized Phase II trial. Eur. Heart J. 2015, 36, 2228–2238. [Google Scholar] [CrossRef] [PubMed]
  213. Mias, C.; Lairez, O.; Trouche, E.; Roncalli, J.; Calise, D.; Seguelas, M.H.; Ordener, C.; Piercecchi-Marti, M.D.; Auge, N.; Salvayre, A.N.; et al. Mesenchymal stem cells promote matrix metalloproteinase secretion by cardiac fibroblasts and reduce cardiac ventricular fibrosis after myocardial infarction. Stem Cells 2009, 27, 2734–2743. [Google Scholar] [CrossRef] [PubMed]
  214. De Lisio, M.; Jensen, T.; Sukiennik, R.A.; Huntsman, H.D.; Boppart, M.D. Substrate and strain alter the muscle-derived mesenchymal stem cell secretome to promote myogenesis. Stem Cell Res. Ther. 2014, 5, 74. [Google Scholar] [CrossRef] [Green Version]
  215. Alexakis, C.; Partridge, T.; Bou-Gharios, G. Implication of the satellite cell in dystrophic muscle fibrosis: A self-perpetuating mechanism of collagen overproduction. Am. J. Physiol. Cell Physiol. 2007, 293, C661–C669. [Google Scholar] [CrossRef] [Green Version]
  216. Ibrahim, A.G.; Cheng, K.; Marban, E. Exosomes as critical agents of cardiac regeneration triggered by cell therapy. Stem Cell Rep. 2014, 2, 606–619. [Google Scholar] [CrossRef] [Green Version]
  217. Barile, L.; Lionetti, V.; Cervio, E.; Matteucci, M.; Gherghiceanu, M.; Popescu, L.M.; Torre, T.; Siclari, F.; Moccetti, T.; Vassalli, G. Extracellular vesicles from human cardiac progenitor cells inhibit cardiomyocyte apoptosis and improve cardiac function after myocardial infarction. Cardiovasc. Res. 2014, 103, 530–541. [Google Scholar] [CrossRef]
  218. Gray, W.D.; French, K.M.; Ghosh-Choudhary, S.; Maxwell, J.T.; Brown, M.E.; Platt, M.O.; Searles, C.D.; Davis, M.E. Identification of therapeutic covariant microRNA clusters in hypoxia-treated cardiac progenitor cell exosomes using systems biology. Circ. Res. 2015, 116, 255–263. [Google Scholar] [CrossRef] [Green Version]
  219. Rao, K.S.; Aronshtam, A.; McElory-Yaggy, K.L.; Bakondi, B.; VanBuren, P.; Sobel, B.E.; Spees, J.L. Human epicardial cell-conditioned medium contains HGF/IgG complexes that phosphorylate RYK and protect against vascular injury. Cardiovasc. Res. 2015, 107, 277–286. [Google Scholar] [CrossRef] [Green Version]
  220. Wei, K.; Serpooshan, V.; Hurtado, C.; Diez-Cunado, M.; Zhao, M.; Maruyama, S.; Zhu, W.; Fajardo, G.; Noseda, M.; Nakamura, K.; et al. Epicardial FSTL1 reconstitution regenerates the adult mammalian heart. Nature 2015, 525, 479–485. [Google Scholar] [CrossRef] [Green Version]
  221. Chen, L.; Wang, Y.; Pan, Y.; Zhang, L.; Shen, C.; Qin, G.; Ashraf, M.; Weintraub, N.; Ma, G.; Tang, Y. Cardiac progenitor-derived exosomes protect ischemic myocardium from acute ischemia/reperfusion injury. Biochem. Biophys. Res. Commun. 2013, 431, 566–571. [Google Scholar] [CrossRef] [Green Version]
  222. Nery, A.A.; Nascimento, I.C.; Glaser, T.; Bassaneze, V.; Krieger, J.E.; Ulrich, H. Human mesenchymal stem cells: From immunophenotyping by flow cytometry to clinical applications. Cytom. A 2013, 83, 48–61. [Google Scholar] [CrossRef] [PubMed]
Ijms 21 08366 g001 550
Figure 1. Characteristics and source of isolation of human mesenchymal stem cells (hMSCs).
Figure 1. Characteristics and source of isolation of human mesenchymal stem cells (hMSCs).
Ijms 21 08366 g001
Table
Table 1. Biological features of hMSCs from different sources, surface markers, and differentiation capacity.
Table 1. Biological features of hMSCs from different sources, surface markers, and differentiation capacity.
SourceCell Surface MarkersLineage DifferentiationReferences
PositiveNegative
Bone marrowSH2, SH3, CD29, CD44, CD49e, CD71, CD73, CD90, CD105, CD106, CD166, CD120a, CD124, STRO-1CD14, CD34, CD45, CD19, CD3, CD31, CD11b, HLA-DRAdipocytes, Chondrocytes,
Osteoblasts, Hepatocyte,
Cardiomyocytes, Pancreatic cells,
Neuronal-like cells		[18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34]
Umbilical cord,
Umbilical cord blood		CK8, CK18, CK19, CD10, CD13, CD29, CD44, CD73, CD90, CD105, CD106, HLA-I, HLA-IICD14, CD31, CD33, CD34, CD45, CD38, CD79, CD133, vWF, HLA-DRAdipocytes, Chondrocytes,
Osteoblasts, Hepatocytes,
Endothelial-like cells, Neuronal-like cells, Pancreatic cells		[6,24,35,36,37,38,39,40,41,42,43,44]
Wharton’s jellyCD13, CD29, CD44, CD73, CD90, CD105, HLA-ICD14, CD34, CD45, CD31, CD79, HLA-II, HLA-DRAdipocytes, Osteoblasts,
Chondrocytes, Hepatocytes,
Neuronal-like cells		[55,56,57,58,59,60,61,62]
Adipose tissueCD13, CD29, CD44, CD71, CD73, CD90, CD105, CD166, HLA-I, HLA-ABC, STRO-1CD10, CD14, CD24, CD31, CD34, CD36, CD38, CD45, CD49, CD117, CD133, SSEA4, CD106, HLA-II, HLA-DRAdipocytes, Chondrocytes,
Osteoblasts, Hepatocyte,
Cardiomyocytes, Pancreatic cells,
Neuronal-like cells,		[24,26,45,46,47,48,49,50,51,52,53,54]
Amniotic fluidSH2, SH3, SH4, CD, CD29, CD44, CD49, CD54, CD58, CD71, CD73, CD90, CD105, CD123, CD166, HLA-ABC, HLA-DRCD10, CD11, CD14, CD31, CD34, CD49, CD50, CD117, HLA-DR, DP, DQ, EMAAdipocytes, Osteoblasts,
Neuronal-like cells		[63,64,65]
Dental tissuesCD29, CD44, CD90, CD105, SH2, SH3, CDHLA-DR, CD117, CD46, DPSC-EZ, DPSC-OGCD10, CD14, CD34, CD45, HLA-DR, Stro-1, NGFRAdipocytes, Chondrocytes,
Osteoblasts, Pancreatic cells,
Melanocytes, Neuronal-like cells		[12,13,66,67,68,69,70,71,72,73,74]
Skin and foreskinCD44, CD90, CD73, CD105, CD166, SSEA4, VimentinCD14, CD45, CD34, c-kit, CD133, SSEA3, OCT-4, TRA 1–60, TRA 1–81, HLA-DRAdipocytes, Osteoblasts,
Chondrocytes, Myoblasts		[75,76]
PlacentaCD29, CD44, CD73, CD90, CD105CD45, CD34, HLA-DRAdipocytes, Osteoblasts,
Endothelial-like cells,
Neuronal-like cells		[36,77]
Salivary glandCD13, CD29, CD44, CD49f, Thy-1, CD90, CD104, p75NGFR, β2-microglobulin, CD130, STRO-1CD34, CD38, CD45, CD133Adipocytes, Chondrocytes,
Osteoblasts, Pancreatic endocrines		[78,79]
Synovial fluidCD10, CD166, CD44, CD54, CD90, CD105, CD147, D7-FIB, STRO-1CD31, CD34, CD45, CD106, CD117, CD166, VEGFR2, Flk-1, CXCR4, BMPR-1A, NGFRAdipocytes, Chondrocytes,
Osteoblasts		[80,81]
Synovial tissuesCD4, CD34, CD45CD44, CD73, CD90, CD105Adipocytes, Chondrocytes,
Osteoblasts		[10,11,82,83]
Nasal polyp tissuesCD105, CD90, CD73, CD54, CD44CD34, CD45, CD117, HLA-DR, PDL-1, PDL-2, CTLA-4, CD106, CD146, CD31Adipocytes, Osteoblasts,
Chondrocytes, Neuronal-like cells		[91,92,93,94]
EndometriumCD73, CD90, CD105, CD146CD34, CD45Adipocytes, Chondrocytes,
Osteoblasts		[84,85]
Limb budCD13, CD29, CD90, CD105, CD106CD3, CD4, CD14, CD15, CD34, CD45, HLA-DROsteoblasts, Adipocytes,
Hepatocytes, Neuronal-like cells		[86]
Peripheral bloodCD44, CD90, CD105, HLA-ABC, CD29, CD73, CD90.1, CD106, CD140αCD45, CD133, CD34, CD19, CD11b, c-kitAdipocytes, Osteoblasts,
Chondrocytes,
Neuronal-like cells		[87,88,89,90]
Table
Table 2. Effect of mesenchymal stem cells in inflammatory-related disease animal models.
Table 2. Effect of mesenchymal stem cells in inflammatory-related disease animal models.
Disease Model (Generation Methods)Up-RegulationDown-RegulationReferences
Graft-vs-host disease;
Depleting endogenous hematopoietic cells by radiation or chemotherapy		Regulatory T cells Auto-antibodies
Inflammatory cytokines
T cell proliferation
TH1 cells		[97,98,99,100,101]
Type 1 diabetes (T1D);
Treatment of streptozotocin		Regulatory T cells
Tissue repair
TH2 cells		Inflammatory T cells
TH1 cells		[102,103,104,105,106]
Pancreatic islet transplantation
Treatment of streptozotocin		Islet survival
Regulatory T cells		TH1 cytokines
T cell responsiveness		[107,108,109]
Experimental autoimmune arthritis
For rheumatoid arthritis, collagen-induced arthritis
For osteoarthritis, meniscectomy; ovariectomy;
treatment of sodium monoiodoacetate		Regulatory T cells
IL-10
TH2 cells		Inflammatory cytokines
T cell responsiveness		[110,111,112,113,114]
Experimental autoimmune encephalomyelitis (EAE);
Induced CNS inflammation by treatment of complete Freund’s adjuvant		TH2T cell responsiveness
CNS infiltration
Auto-antibodies
TH1/TH17 cells		[115,116,117,118]
Inflammatory bowel disease (IBD);
1, Treatment with dextran sulfate sodium added to drinking water
2, Intrarectal administration of trinitrobenzene sulfonic acid		Anti-inflammatory cytokines
Regulatory T cells
FasL-mediated T cell apoptosis		Inflammatory T cells
Inflammatory cytokines
Intestinal CD4+ T cell infiltration
Growth factor expression
T cell responsiveness		[111,119,120,121,122,123]
Systemic lupus erythematosus (SLE);
1, Progeny of a breeding pair consisting of a New Zealand Black mouse and New Zealand White mouse.
2, Mutation in the gene encoding Fas on the MRL strain background		Regulatory T cells
Anti-inflammatory cytokines		Anti-DNA antibodies
T cell frequency
TH17 cells
Plasma cells
Inflammatory cytokines		[124,125,126,127]
Chronic rhinosinusitis with nasal polyps (CRSwNP);
For eosinophilic CRSwNP,
Ovalbumin and Staphylococcus aureus enterotoxin B
For non-eosinophilic CRSwNP,
Lipopolysaccharide		Regulatory T cells
IL-10		CD4+ and CD8+ T cell proliferation
IL-2, TNF-α, IFN-γ		[49,128,129,130,131,132]
Table
Table 3. Effect of mesenchymal stem cells in fibrosis-related disease animal models.
Table 3. Effect of mesenchymal stem cells in fibrosis-related disease animal models.
Disease ModelRoute of DeliveryTherapeutic EffectReferences
Lung
Bronchopulmoary dysplasia
Hyperoxia neonatal lung injuryIntravenous,
Intratracheal,
intraperitoneal		Protection of alveoli,
Reduce and decrease inflammation, pulmonary injury, hypertension and fibrosis
Vascular growth,
Increase survival		[166,167,168,169]
Acute respiratory distress syndrome
Bacterial pneumoniaIntravenousImprove oxygenation (PaO2/FiO2w)
Decrease pulmonary edema		[162]
LPS-induced inflammationIntravenousReduce histopathological changes,
Increased survival,
Protection of alveoli,
Lung mechanics improve		[170]
Chronic lower respiratory disease
Cigarette smoke exposureIntratracheal
/Intravenous		Decrease tracheal responsiveness, inflammatory cytokines, and inflammatory cell infiltration[163]
LPS, cigarette smoke, and 17% oxygen exposureIntratrachealDecrease in inflammatory cytokines,
Increase in ECM production		[171]
Cycstic fibrosis
Naphthalene-induced lung injuryIntravenousLittle to no level of CFTR dependent chloride secretion[164]
Idiopathic pulmonary fibrosis
Bleomycin-induced lung injuryIntratrachealDecrease fibrosis and airway inflammation[165]
Liver
Chronic hepatitis BIntravenousImprovement of liver function and MELD score
Reduce ascites		[172]
Primary biliary cirrhosisIntravenousDecrease in serum ALP and γ-GGT[173]
Hepatitis C virus cirrhosisIntravenous infusion,
Peripheral vein		Improvement in liver function;
Frequency of encephalopathy, jaundice, ascites, bleeding tendency, and lower limb edema		[174,175]
Hepatitis B virus cirrhosisHepatic arteryImprovement in liver function[176]
Pancreas
Dibutyltin dichloridePenile vein,
Jugular vein		Immunomodulatory effect
Inhibition of activation of pancreatic satellite cells
Anti-apoptotic effect		[177,178,179]
Heart
Ischemic heart failureIntramyocardialReduction of infarct scar, inflammation, vascular permeability, fibrosis in scarred tissues
Improve LVEF and endothelial function
Increase cardiac function, survival and angiogenesis		[180,181,182,183,184,185]
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Share and Cite

MDPI and ACS Style

Ryu, J.-S.; Jeong, E.-J.; Kim, J.-Y.; Park, S.J.; Ju, W.S.; Kim, C.-H.; Kim, J.-S.; Choo, Y.-K. Application of Mesenchymal Stem Cells in Inflammatory and Fibrotic Diseases. Int. J. Mol. Sci. 2020, 21, 8366. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21218366

AMA Style

Ryu J-S, Jeong E-J, Kim J-Y, Park SJ, Ju WS, Kim C-H, Kim J-S, Choo Y-K. Application of Mesenchymal Stem Cells in Inflammatory and Fibrotic Diseases. International Journal of Molecular Sciences. 2020; 21(21):8366. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21218366

Chicago/Turabian Style

Ryu, Jae-Sung, Eun-Jeong Jeong, Jong-Yeup Kim, Soon Ju Park, Won Seok Ju, Chang-Hyun Kim, Jang-Seong Kim, and Young-Kug Choo. 2020. "Application of Mesenchymal Stem Cells in Inflammatory and Fibrotic Diseases" International Journal of Molecular Sciences 21, no. 21: 8366. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21218366

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop