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Special Issue "Stem Cell Activation in Adult Organism 2.0"

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Biology".

Deadline for manuscript submissions: 30 April 2022.

Special Issue Editors

Prof. Dr. Daniela Salvatori
E-Mail Website
Guest Editor
Department of Clinical Sciences, Anatomy and Physiology, Faculty of Veterinary Medicine, Utrecht University, 3584 Utrecht, The Netherlands
Interests: pluripotent stem cells; cardiology; mouse models; gene therapy; nuclear reprogramming
Prof. Dr. Wilhelm Bloch
E-Mail Website
Guest Editor
Institute of Cardiology and Sports Medicine, Department of Molecular and Cellular Sport Medicine, German Sport University Cologne, Am Sportpark Müngersdorf 6, 50933 Cologne, Germany
Interests: exercise biology; stem and progenitor mediated tissue adaptation; epigenetics and sport; mechanism of physical training in oncology; muscle growth and repair; vascular biology
Special Issues and Collections in MDPI journals

Special Issue Information

Dear Colleagues,

This Special Issue is the continuation of our 2015 Special Issue, “Stem Cell Activation in Adult Organism” https://0-www-mdpi-com.brum.beds.ac.uk/journal/ijms/special_issues/stem_cell_active.

The research on stem cells has developed as a promising area of biology in the last few decades. Meanwhile, the potential of stem cell-based tissue regeneration in the adult organism is recognized for nearly all organs and tissues, such as muscle, heart, brain, lung, mesenchymal, epithelial, and connective tissues. At the beginning of stem cell research for regeneration and repair in adults, a strong focus was given to embryonic stem cells, followed by a search for adult stem cell populations, which can be used, by virtue of their high differentiation potential, to replace organ and tissue specific cell types. In the last few years, it has been recognized that the stem cell potential of terminal, differentiated cells can be rescued by reprogramming. While first strategies are orientated for the ex vivo reprogramming of terminal differentiated cells into multipotent stem cells, increasing knowledge about the reprogramming mechanisms and the influencing factors supporting mobilization of tissue stem cells or the reprogramming of tissue specific cells to stem and progenitor cells, allows us to currently and additionally develop strategies for the endogenous mobilization of stem cells and the reprogramming of differentiated cells from different tissues. Local and systemic factors, such as cytokines, the extracellular matrix, and supporting cells are crucial for understanding of mobilization strategies. These strategies can be used for systemic and local stem cell-based therapy.

This Special Issue, “Stem Cell Activation in Adult Organism 2.0,” will cover a selection of recent research topics and current review articles in the field of stem cell research for the regeneration and repair of different tissues and organs in the adult organism. Experimental papers, up-to-date review articles, and commentaries are all welcome.

Prof. Dr. Daniela Salvatori
Prof. Dr. Wilhelm Bloch
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All papers will be peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • adult stem cell
  • reprogramming
  • stem cell therapy
  • signaling and mechanism
  • growth factors
  • extra cellular matrix
  • homing
  • transdifferentiation

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Published Papers (25 papers)

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Editorial

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Editorial
Stem Cell Activation in Adult Organisms
Int. J. Mol. Sci. 2016, 17(7), 1005; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms17071005 - 24 Jun 2016
Viewed by 2137
Abstract
Stem cells are responsible for the organ and tissue development, growth and maintenance from embryonic stage up to late adult life.[...] Full article
(This article belongs to the Special Issue Stem Cell Activation in Adult Organism)

Research

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Article
Immunomodulatory Properties of Umbilical Cord Blood-Derived Small Extracellular Vesicles and Their Therapeutic Potential for Inflammatory Skin Disorders
Int. J. Mol. Sci. 2021, 22(18), 9797; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22189797 - 10 Sep 2021
Viewed by 369
Abstract
Umbilical cord blood (UCB) has long been seen as a rich source of naïve cells with strong regenerative potential, likely mediated by paracrine signals. More recently, small extracellular vesicles (sEV), such as exosomes, have been shown to play essential roles in cell-to-cell communication, [...] Read more.
Umbilical cord blood (UCB) has long been seen as a rich source of naïve cells with strong regenerative potential, likely mediated by paracrine signals. More recently, small extracellular vesicles (sEV), such as exosomes, have been shown to play essential roles in cell-to-cell communication, via the transport of numerous molecules, including small RNAs. Often explored for their potential as biomarkers, sEV are now known to have regenerative and immunomodulating characteristics, particularly if isolated from stem cell-rich tissues. In this study, we aim to characterize the immunomodulating properties of umbilical cord blood mononuclear cell-derived sEV (UCB-MNC-sEV) and explore their therapeutic potential for inflammatory skin diseases. UCB-MNC-sEV were shown to shift macrophages toward an anti-inflammatory phenotype, which in turn exert paracrine effects on fibroblasts, despite previous inflammatory stimuli. Additionally, the incubation of PBMC with UCB-MNC-sEV resulted in a reduction of total CD4+ and CD8+ T-cell proliferation and cytokine release, while specifically supporting the development of regulatory T-cells (Treg), by influencing FOXP3 expression. In a 3D model of psoriatic skin, UCB-MNC-sEV reduced the expression of inflammatory and psoriatic markers IL6, IL8, CXCL10, COX2, S100A7, and DEFB4. In vivo, UCB-MNC-sEV significantly prevented or reversed acanthosis in imiquimod-induced psoriasis, and tendentially increased the number of Treg in skin, without having an overall impact on disease burden. This work provides evidence for the anti-inflammatory and tolerogenic effect of UCB-MNC-sEV, which may be harnessed for the treatment of Th17-driven inflammatory skin diseases, such as psoriasis. Full article
(This article belongs to the Special Issue Stem Cell Activation in Adult Organism 2.0)
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Article
The Phosphonate Derivative of C60 Fullerene Induces Differentiation towards the Myogenic Lineage in Human Adipose-Derived Mesenchymal Stem Cells
Int. J. Mol. Sci. 2021, 22(17), 9284; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22179284 - 27 Aug 2021
Viewed by 412
Abstract
Inductors of myogenic stem cell differentiation attract attention, as they can be used to treat myodystrophies and post-traumatic injuries. Functionalization of fullerenes makes it possible to obtain water-soluble derivatives with targeted biochemical activity. This study examined the effects of the phosphonate C60 [...] Read more.
Inductors of myogenic stem cell differentiation attract attention, as they can be used to treat myodystrophies and post-traumatic injuries. Functionalization of fullerenes makes it possible to obtain water-soluble derivatives with targeted biochemical activity. This study examined the effects of the phosphonate C60 fullerene derivatives on the expression of myogenic transcription factors and myogenic differentiation of human mesenchymal stem cells (MSCs). Uptake of the phosphonate C60 fullerene derivatives in human MSCs, intracellular ROS visualization, superoxide scavenging potential, and the expression of myogenic, adipogenic, and osteogenic differentiation genes were studied. The prolonged MSC incubation (within 7–14 days) with the C60 pentaphoshonate potassium salt promoted their differentiation towards the myogenic lineage. The transcription factors and gene expressions determining myogenic differentiation (MYOD1, MYOG, MYF5, and MRF4) increased, while the expression of osteogenic differentiation factors (BMP2, BMP4, RUNX2, SPP1, and OCN) and adipogenic differentiation factors (CEBPB, LPL, and AP2 (FABP4)) was reduced or did not change. The stimulation of autophagy may be one of the factors contributing to the increased expression of myogenic differentiation genes in MSCs. Autophagy may be caused by intracellular alkalosis and/or short-term intracellular oxidative stress. Full article
(This article belongs to the Special Issue Stem Cell Activation in Adult Organism 2.0)
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Article
Mesenchymal Stem Cells Ameliorated Glucolipotoxicity in HUVECs through TSG-6
Int. J. Mol. Sci. 2016, 17(4), 483; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms17040483 - 01 Apr 2016
Cited by 14 | Viewed by 3077
Abstract
Glucolipotoxicity is one of the critical causal factors of diabetic complications. Whether mesenchymal stem cells (MSCs) have effects on glucolipotoxicity in human umbilical vein endothelial cells (HUVECs) and mechanisms involved are unclear. Thirty mM glucose plus 100 μM palmitic acid was used to [...] Read more.
Glucolipotoxicity is one of the critical causal factors of diabetic complications. Whether mesenchymal stem cells (MSCs) have effects on glucolipotoxicity in human umbilical vein endothelial cells (HUVECs) and mechanisms involved are unclear. Thirty mM glucose plus 100 μM palmitic acid was used to induce glucolipotoxicity in HUVECs. MSCs and HUVECs were co-cultured at the ratio of 1:5 via Transwell system. The mRNA expressions of inflammatory factors were detected by RT-qPCR. The productions of reactive oxygen species (ROS), cell cycle and apoptosis were analyzed by flow cytometry. The tumor necrosis factor-α stimulated protein 6 (TSG-6) was knockdown in MSCs by RNA interference. High glucose and palmitic acid remarkably impaired cell viability and tube formation capacity, as well as increased the mRNA expression of inflammatory factors, ROS levels, and cell apoptosis in HUVECs. MSC co-cultivation ameliorated these detrimental effects in HUVECs, but no effect on ROS production. Moreover, TSG-6 was dramatically up-regulated by high glucose and fatty acid stimulation in both MSCs and HUVECs. TSG-6 knockdown partially abolished the protection mediated by MSCs. MSCs had protective effects on high glucose and palmitic acid induced glucolipotoxicity in HUVECs, and TSG-6 secreted by MSCs was likely to play an important role in this process. Full article
(This article belongs to the Special Issue Stem Cell Activation in Adult Organism)
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Article
Mitotic Diversity in Homeostatic Human Interfollicular Epidermis
Int. J. Mol. Sci. 2016, 17(2), 167; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms17020167 - 28 Jan 2016
Cited by 8 | Viewed by 3814
Abstract
Despite decades of skin research, regulation of proliferation and homeostasis in human epidermis is still insufficiently understood. To address the role of mitoses in tissue regulation, we utilized human long-term skin equivalents and systematically assessed mitoses during early epidermal development and long-term epidermal [...] Read more.
Despite decades of skin research, regulation of proliferation and homeostasis in human epidermis is still insufficiently understood. To address the role of mitoses in tissue regulation, we utilized human long-term skin equivalents and systematically assessed mitoses during early epidermal development and long-term epidermal regeneration. We now demonstrate four different orientations: (1) horizontal, i.e., parallel to the basement membrane (BM) and suggestive of symmetric divisions; (2) oblique with an angle of 45°–70°; or (3) perpendicular, suggestive of asymmetric division. In addition, we demonstrate a fourth substantial fraction of suprabasal mitoses, many of which are committed to differentiation (Keratin K10-positive). As verified also for normal human skin, this spatial mitotic organization is part of the regulatory program of human epidermal tissue homeostasis. As a potential marker for asymmetric division, we investigated for Numb and found that it was evenly spread in almost all undifferentiated keratinocytes, but indeed asymmetrically distributed in some mitoses and particularly frequent under differentiation-repressing low-calcium conditions. Numb deletion (stable knockdown by CRISPR/Cas9), however, did not affect proliferation, neither in a three-day follow up study by life cell imaging nor during a 14-day culture period, suggesting that Numb is not essential for the general control of keratinocyte division. Full article
(This article belongs to the Special Issue Stem Cell Activation in Adult Organism)
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Article
Mesenchymal Stem Cells Preserve Working Memory in the 3xTg-AD Mouse Model of Alzheimer’s Disease
Int. J. Mol. Sci. 2016, 17(2), 152; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms17020152 - 25 Jan 2016
Cited by 29 | Viewed by 3817
Abstract
The transplantation of stem cells may have a therapeutic effect on the pathogenesis and progression of neurodegenerative disorders. In the present study, we transplanted human mesenchymal stem cells (MSCs) into the lateral ventricle of a triple transgenic mouse model of Alzheimer´s disease (3xTg-AD) [...] Read more.
The transplantation of stem cells may have a therapeutic effect on the pathogenesis and progression of neurodegenerative disorders. In the present study, we transplanted human mesenchymal stem cells (MSCs) into the lateral ventricle of a triple transgenic mouse model of Alzheimer´s disease (3xTg-AD) at the age of eight months. We evaluated spatial reference and working memory after MSC treatment and the possible underlying mechanisms, such as the influence of transplanted MSCs on neurogenesis in the subventricular zone (SVZ) and the expression levels of a 56 kDa oligomer of amyloid β (Aβ*56), glutamine synthetase (GS) and glutamate transporters (Glutamate aspartate transporter (GLAST) and Glutamate transporter-1 (GLT-1)) in the entorhinal and prefrontal cortices and the hippocampus. At 14 months of age we observed the preservation of working memory in MSC-treated 3xTg-AD mice, suggesting that such preservation might be due to the protective effect of MSCs on GS levels and the considerable downregulation of Aβ*56 levels in the entorhinal cortex. These changes were observed six months after transplantation, accompanied by clusters of proliferating cells in the SVZ. Since the grafted cells did not survive for the whole experimental period, it is likely that the observed effects could have been transiently more pronounced at earlier time points than at six months after cell application. Full article
(This article belongs to the Special Issue Stem Cell Activation in Adult Organism)
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Article
Survivin Modulates Squamous Cell Carcinoma-Derived Stem-Like Cell Proliferation, Viability and Tumor Formation in Vivo
Int. J. Mol. Sci. 2016, 17(1), 89; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms17010089 - 12 Jan 2016
Cited by 10 | Viewed by 2960
Abstract
Squamous Cell Carcinoma-derived Stem-like Cells (SCC-SC) originate from alterations in keratinocyte stem cells (KSC) gene expression and sustain tumor development, invasion and recurrence. Since survivin, a KSC marker, is highly expressed in SCC-SC, we evaluate its role in SCC-SC cell growth and SCC [...] Read more.
Squamous Cell Carcinoma-derived Stem-like Cells (SCC-SC) originate from alterations in keratinocyte stem cells (KSC) gene expression and sustain tumor development, invasion and recurrence. Since survivin, a KSC marker, is highly expressed in SCC-SC, we evaluate its role in SCC-SC cell growth and SCC models. Survivin silencing by siRNA decreases clonal growth of SCC keratinocytes and viability of total, rapidly adhering (RAD) and non-RAD (NRAD) cells from primary SCC. Similarly, survivin silencing reduces the expression of stem cell markers (OCT4, NOTCH1, CD133, β1-integrin), while it increases the level of differentiation markers (K10, involucrin). Moreover, survivin silencing improves the malignant phenotype of SCC 3D-reconstruct, as demonstrated by reduced epidermal thickness, lower Ki-67 positive cell number, and decreased expression of MMP9 and psoriasin. Furthermore, survivin depletion by siRNA in RasG12V-IκBα-derived tumors leads to smaller tumor formation characterized by lower mitotic index and reduced expression of the tumor-associated marker HIF1α, VEGF and CD51. Therefore, our results indicate survivin as a key gene in regulating SCC cancer stem cell formation and cSCC development. Full article
(This article belongs to the Special Issue Stem Cell Activation in Adult Organism)
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Article
Porcine Adipose-Derived Mesenchymal Stem Cells Retain Their Stem Cell Characteristics and Cell Activities While Enhancing the Expression of Liver-Specific Genes after Acute Liver Failure
Int. J. Mol. Sci. 2016, 17(1), 62; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms17010062 - 05 Jan 2016
Cited by 13 | Viewed by 3071
Abstract
Acute liver failure (ALF) is a kind of complicated syndrome. Furthermore, adipose-derived mesenchymal stem cells (ADMSCs) can serve as a useful cell resource for autotransplantation due to their abundance and micro-invasive accessability. However, it is unknown how ALF will influence the characteristics of [...] Read more.
Acute liver failure (ALF) is a kind of complicated syndrome. Furthermore, adipose-derived mesenchymal stem cells (ADMSCs) can serve as a useful cell resource for autotransplantation due to their abundance and micro-invasive accessability. However, it is unknown how ALF will influence the characteristics of ADMSCs and whether ADMSCs from patients suffering from end-stage liver diseases are potential candidates for autotransplantation. This study was designed to compare various properties of ALF-derived ADMSCs with normal ADMSCs in pig models, with regard to their cellular morphology, cell proliferative ability, cell apoptosis, expression of surface antigens, mitochondrial and lysosomal activities, multilineage potency, and expression of liver-specific genes. Our results showed that ALF does not influence the stem cell characteristics and cell activities of ADMSCs. Intriguingly, the expression levels of several liver-specific genes in ALF-derived ADMSCs are higher than in normal ADMSCs. In conclusion, our findings indicate that the stem cell characteristics and cell activities of ADMSCs were not altered by ALF and these cells can serve as a new source for regenerative medicine. Full article
(This article belongs to the Special Issue Stem Cell Activation in Adult Organism)
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Communication
Stem Cell Replacement Improves Expression of SMP30 in db/db Mice
Int. J. Mol. Sci. 2015, 16(12), 29971-29979; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms161226217 - 16 Dec 2015
Cited by 2 | Viewed by 2883
Abstract
We have previously reported that replacing bone marrow stem cells may improve hyperglycemia and oxidative stress in db/db mice, a type 2 diabetic mouse model. Senescence marker protein 30 (SMP30) is an antioxidant protein that decreases with aging. However, it has not been [...] Read more.
We have previously reported that replacing bone marrow stem cells may improve hyperglycemia and oxidative stress in db/db mice, a type 2 diabetic mouse model. Senescence marker protein 30 (SMP30) is an antioxidant protein that decreases with aging. However, it has not been clear whether SMP30 decreases in the livers of obese mice, and whether stem cell replacement would improve SMP30 expression in the liver. Bone marrow stem cells of db/db mice were replaced with the bone marrow stem cells of C57BL/6 mice. Plasma cytokine and insulin levels were measured, and glycogen content, expression of SMP30, and fibrosis in the liver were assessed. Our results showed that stem cell replacement increased the expression of SMP30 in the liver, resulting from decreased plasma inflammation cytokines and hyperinsulinemia in db/db mice. This is the first report that stem cell replacement increased the expression of SMP30 in the liver, and may help prevent fibrosis in the liver of db/db mice. Full article
(This article belongs to the Special Issue Stem Cell Activation in Adult Organism)
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Article
Connexin 50 Expression in Ependymal Stem Progenitor Cells after Spinal Cord Injury Activation
Int. J. Mol. Sci. 2015, 16(11), 26608-26618; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms161125981 - 06 Nov 2015
Cited by 9 | Viewed by 3456
Abstract
Ion channels included in the family of Connexins (Cx) help to control cell proliferation and differentiation of neuronal progenitors. Here we explored the role of Connexin 50 (Cx50) in cell fate modulation of adult spinal cord derived neural precursors located in the ependymal [...] Read more.
Ion channels included in the family of Connexins (Cx) help to control cell proliferation and differentiation of neuronal progenitors. Here we explored the role of Connexin 50 (Cx50) in cell fate modulation of adult spinal cord derived neural precursors located in the ependymal canal (epSPC). epSPC from non-injured animals showed high expression levels of Cx50 compared to epSPC from animals with spinal cord injury (SCI) (epSPCi). When epSPC or epSPCi were induced to spontaneously differentiate in vitro we found that Cx50 favors glial cell fate, since higher expression levels, endogenous or by over-expression of Cx50, augmented the expression of the astrocyte marker GFAP and impaired the neuronal marker Tuj1. Cx50 was found in both the cytoplasm and nucleus of glial cells, astrocytes and oligodendrocyte-derived cells. Similar expression patterns were found in primary cultures of mature astrocytes. In addition, opposite expression profile for nuclear Cx50 was observed when epSPC and activated epSPCi were conducted to differentiate into mature oligodendrocytes, suggesting a different role for this ion channel in spinal cord beyond cell-to-cell communication. In vivo detection of Cx50 by immunohistochemistry showed a defined location in gray matter in non-injured tissues and at the epicenter of the injury after SCI. epSPCi transplantation, which accelerates locomotion regeneration by a neuroprotective effect after acute SCI is associated with a lower signal of Cx50 within the injured area, suggesting a minor or detrimental contribution of this ion channel in spinal cord regeneration by activated epSPCi. Full article
(This article belongs to the Special Issue Stem Cell Activation in Adult Organism)
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Article
Isolation and Culture of Pig Spermatogonial Stem Cells and Their in Vitro Differentiation into Neuron-Like Cells and Adipocytes
Int. J. Mol. Sci. 2015, 16(11), 26333-26346; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms161125958 - 04 Nov 2015
Cited by 17 | Viewed by 3714
Abstract
Spermatogonial stem cells (SSCs) renew themselves throughout the life of an organism and also differentiate into sperm in the adult. They are multipopent and therefore, can be induced to differentiate into many cells types in vitro. SSCs from pigs, considered an ideal animal [...] Read more.
Spermatogonial stem cells (SSCs) renew themselves throughout the life of an organism and also differentiate into sperm in the adult. They are multipopent and therefore, can be induced to differentiate into many cells types in vitro. SSCs from pigs, considered an ideal animal model, are used in studies of male infertility, regenerative medicine, and preparation of transgenic animals. Here, we report on a culture system for porcine SSCs and the differentiation of these cells into neuron-like cells and adipocytes. SSCs and Sertoli cells were isolated from neonatal piglet testis by differential adhesion and SSCs were cultured on a feeder layer of Sertoli cells. Third-generation SSCs were induced to differentiate into neuron-like cells by addition of retinoic acid, β-mercaptoethanol, and 3-isobutyl-1-methylxanthine (IBMX) to the induction media and into adipocytes by the addition of hexadecadrol, insulin, and IBMX to the induction media. The differentiated cells were characterized by biochemical staining, qRT-PCR, and immunocytochemistry. The cells were positive for SSC markers, including alkaline phosphatase and SSC-specific genes, consistent with the cells being undifferentiated. The isolated SSCs survived on the Sertoli cells for 15 generations. Karyotyping confirmed that the chromosomal number of the SSCs were normal for pig (2n = 38, n = 19). Pig SSCs were successfully induced into neuron-like cells eight days after induction and into adipocytes 22 days after induction as determined by biochemical and immunocytochemical staining. qPCR results also support this conclusion. The nervous tissue markers genes, Nestin and β-tubulin, were expressed in the neuron-like cells and the adipocyte marker genes, PPARγ and C/EBPα, were expressed in the adipocytes. Full article
(This article belongs to the Special Issue Stem Cell Activation in Adult Organism)
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Article
Secreted Frizzled-Related Protein Promotes Bone Regeneration by Human Bone Marrow-Derived Mesenchymal Stem Cells
Int. J. Mol. Sci. 2015, 16(10), 23250-23258; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms161023250 - 25 Sep 2015
Cited by 4 | Viewed by 3893
Abstract
Secreted frizzled-related protein (sFRP)-3 is a negative regulator of Wnt signaling in human mesenchymal stem cells (hMSCs). The present study investigated the effects sFRP-3 on osteogenic differentiation by assessing osteogenic gene expression in hMSCs in vitro and by examining bone regeneration in a [...] Read more.
Secreted frizzled-related protein (sFRP)-3 is a negative regulator of Wnt signaling in human mesenchymal stem cells (hMSCs). The present study investigated the effects sFRP-3 on osteogenic differentiation by assessing osteogenic gene expression in hMSCs in vitro and by examining bone regeneration in a rat bone defect model. sFRP-3 treatment induced osteogenic differentiation in hMSCs as determined by alkaline phosphatase, collagen type I, osteocalcin, and Runt-related transcription factor 2 gene expression. hMSCs with or without sFRP-3 were implanted into a rat calvarial bone defect; a radiographic analysis by micro-computed tomography and histological analysis 4 and 8 weeks after implantation showed greater bone regeneration in the sFRP(+) than in the sFRP(−) group. These results suggest that modulation of Wnt signaling contributes to osteogenic differentiation in hMSCs. Specifically, sFRP-3 induces osteoblastic differentiation of cultured MSCs and bone regeneration in a calvarial bone defect, suggesting that it can be a useful agent for the treatment of bone defects. Full article
(This article belongs to the Special Issue Stem Cell Activation in Adult Organism)
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Article
BMP3 Alone and Together with TGF-β Promote the Differentiation of Human Mesenchymal Stem Cells into a Nucleus Pulposus-Like Phenotype
Int. J. Mol. Sci. 2015, 16(9), 20344-20359; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms160920344 - 27 Aug 2015
Cited by 21 | Viewed by 3184
Abstract
Human mesenchymal stem cells (MSCs) have the potential to differentiate into nucleus pulposus (NP)-like cells under specific stimulatory conditions. Thus far, the effects of bone morphogenetic protein 3 (BMP3) and the cocktail effects of BMP3 and transforming growth factor (TGF)-β on MSC proliferation [...] Read more.
Human mesenchymal stem cells (MSCs) have the potential to differentiate into nucleus pulposus (NP)-like cells under specific stimulatory conditions. Thus far, the effects of bone morphogenetic protein 3 (BMP3) and the cocktail effects of BMP3 and transforming growth factor (TGF)-β on MSC proliferation and differentiation remain obscure. Therefore, this study was designed to clarify these unknowns. MSCs were cultured with various gradients of BMP3 and BMP3/TGF-β, and compared with cultures in basal and TGF-β media. Cell proliferation, glycosaminoglycan (GAG) content, gene expression, and signaling proteins were measured to assess the effects of BMP3 and BMP3/TGF-β on MSCs. Cell number and GAG content increased upon the addition of BMP3 in a dose-dependent manner. The expression of COL2A1, ACAN, SOX9, and KRT19 increased following induction with BMP3 and TGF-β, in contrast to that of COL1A1, ALP, OPN, and COMP. Smad3 phosphorylation was upregulated by BMP3 and TGF-β, but BMP3 did not affect the phosphorylation of extracellular-signal regulated kinase (ERK) 1/2 or c-Jun N-terminal kinase (JNK). Our results reveal that BMP3 enhances MSC proliferation and differentiation into NP-like cells, as indicated by increased cell numbers and specific gene expressions, and may also cooperate with TGF-β induced positive effects. These actions are likely related to the activation of TGF-β signaling pathway. Full article
(This article belongs to the Special Issue Stem Cell Activation in Adult Organism)
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Article
Human Dermal Stem/Progenitor Cell-Derived Conditioned Medium Improves Senescent Human Dermal Fibroblasts
Int. J. Mol. Sci. 2015, 16(8), 19027-19039; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms160819027 - 13 Aug 2015
Cited by 8 | Viewed by 3420
Abstract
Adult skin stem cells are recognized as potential therapeutics to rejuvenate aged skin. We previously demonstrated that human dermal stem/progenitor cells (hDSPCs) with multipotent capacity could be enriched from human dermal fibroblasts using collagen type IV. However, the effects of hDSPCs on cellular [...] Read more.
Adult skin stem cells are recognized as potential therapeutics to rejuvenate aged skin. We previously demonstrated that human dermal stem/progenitor cells (hDSPCs) with multipotent capacity could be enriched from human dermal fibroblasts using collagen type IV. However, the effects of hDSPCs on cellular senescence remain to be elucidated. In the present study, we investigated whether conditioned medium (CM) collected from hDSPC cultures (hDSPC-CM) exhibits beneficial effects on senescent fibroblasts. We found that hDSPC-CM promoted proliferation and decreased the expression level of senescence-associated β-galactosidase in senescent fibroblasts. In addition, p53 phosphorylation and p21 expression were significantly reduced in senescent fibroblasts treated with hDSPC-CM. hDSPC-CM restored the expression levels of collagen type I, collagen type III, and tissue inhibitor of metalloproteinase, and antagonized the increase of matrix metalloproteinase 1 expression. Finally, we demonstrated that hDSPC-CM significantly reduced reactive oxygen species levels by specifically up-regulating the expression level of superoxide dismutase 2. Taken together, these data suggest that hDSPC-CM can be applied as a potential therapeutic agent for improving human aged skin. Full article
(This article belongs to the Special Issue Stem Cell Activation in Adult Organism)
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Article
Human Adipose-Derived Mesenchymal Progenitor Cells Engraft into Rabbit Articular Cartilage
Int. J. Mol. Sci. 2015, 16(6), 12076-12091; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms160612076 - 27 May 2015
Cited by 44 | Viewed by 5458
Abstract
Mesenchymal stem cells (MSCs) are known to have the potential for articular cartilage regeneration, and are suggested for the treatment of osteoarthritis (OA). Here, we investigated whether intra-articular injection of xenogeneic human adipose-derived mesenchymal progenitor cells (haMPCs) promoted articular cartilage repair in rabbit [...] Read more.
Mesenchymal stem cells (MSCs) are known to have the potential for articular cartilage regeneration, and are suggested for the treatment of osteoarthritis (OA). Here, we investigated whether intra-articular injection of xenogeneic human adipose-derived mesenchymal progenitor cells (haMPCs) promoted articular cartilage repair in rabbit OA model and engrafted into rabbit articular cartilage. The haMPCs were cultured in vitro, and phenotypes and differentiation characteristics of cells were evaluated. OA was induced surgically by anterior cruciate ligament transection (ACLT) and medical meniscectomy of knee joints. At six weeks following surgery, hyaluronic acid (HA) or haMPCs was injected into the knee joints, the contralateral knee served as normal control. All animals were sacrificed at the 16th week post-surgery. Assessments were carried out by macroscopic examination, hematoxylin/eosin (HE) and Safranin-O/Fast green stainings and immunohistochemistry. The data showed that haMPC treatment promoted cartilage repair. Signals of human mitochondrial can be directly detected in haMPC treated cartilage. The haMPCs expressed human leukocyte antigen I (HLA-I) but not HLA-II-DR in vivo. These results suggest that intra-articular injection of haMPCs promotes regeneration of articular cartilage in rabbit OA model, and support the notion that MPCs are transplantable between HLA-incompatible individuals. Full article
(This article belongs to the Special Issue Stem Cell Activation in Adult Organism)
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Article
MicroRNA Expression Profile of Neural Progenitor-Like Cells Derived from Rat Bone Marrow Mesenchymal Stem Cells under the Influence of IGF-1, bFGF and EGF
Int. J. Mol. Sci. 2015, 16(5), 9693-9718; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms16059693 - 29 Apr 2015
Cited by 22 | Viewed by 4760
Abstract
Insulin-like growth factor 1 (IGF-1) enhances cellular proliferation and reduces apoptosis during the early differentiation of bone marrow derived mesenchymal stem cells (BMSCs) into neural progenitor-like cells (NPCs) in the presence of epidermal growth factor (EGF) and basic fibroblast growth factor (bFGF). BMSCs [...] Read more.
Insulin-like growth factor 1 (IGF-1) enhances cellular proliferation and reduces apoptosis during the early differentiation of bone marrow derived mesenchymal stem cells (BMSCs) into neural progenitor-like cells (NPCs) in the presence of epidermal growth factor (EGF) and basic fibroblast growth factor (bFGF). BMSCs were differentiated in three groups of growth factors: (A) EGF + bFGF, (B) EGF + bFGF + IGF-1, and (C) without growth factor. To unravel the molecular mechanisms of the NPCs derivation, microarray analysis using GeneChip® miRNA arrays was performed. The profiles were compared among the groups. Annotated microRNA fingerprints (GSE60060) delineated 46 microRNAs temporally up-regulated or down-regulated compared to group C. The expressions of selected microRNAs were validated by real-time PCR. Among the 46 microRNAs, 30 were consistently expressed for minimum of two consecutive time intervals. In Group B, only miR-496 was up-regulated and 12 microRNAs, including the let-7 family, miR-1224, miR-125a-3p, miR-214, miR-22, miR-320, miR-708, and miR-93, were down-regulated. Bioinformatics analysis reveals that some of these microRNAs (miR-22, miR-214, miR-125a-3p, miR-320 and let-7 family) are associated with reduction of apoptosis. Here, we summarize the roles of key microRNAs associated with IGF-1 in the differentiation of BMSCs into NPCs. These findings may provide clues to further our understanding of the mechanisms and roles of microRNAs as key regulators of BMSC-derived NPC maintenance. Full article
(This article belongs to the Special Issue Stem Cell Activation in Adult Organism)
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Review

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Review
Cell-Based Regeneration and Treatment of Liver Diseases
Int. J. Mol. Sci. 2021, 22(19), 10276; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms221910276 - 24 Sep 2021
Viewed by 313
Abstract
The liver, in combination with a functional biliary system, is responsible for maintaining a great number of vital body functions. However, acute and chronic liver diseases may lead to irreversible liver damage and, ultimately, liver failure. At the moment, the best curative option [...] Read more.
The liver, in combination with a functional biliary system, is responsible for maintaining a great number of vital body functions. However, acute and chronic liver diseases may lead to irreversible liver damage and, ultimately, liver failure. At the moment, the best curative option for patients suffering from end-stage liver disease is liver transplantation. However, the number of donor livers required by far surpasses the supply, leading to a significant organ shortage. Cellular therapies play an increasing role in the restoration of organ function and can be integrated into organ transplantation protocols. Different types and sources of stem cells are considered for this purpose, but highly specific immune cells are also the focus of attention when developing individualized therapies. In-depth knowledge of the underlying mechanisms governing cell differentiation and engraftment is crucial for clinical implementation. Additionally, novel technologies such as ex vivo machine perfusion and recent developments in tissue engineering may hold promising potential for the implementation of cell-based therapies to restore proper organ function. Full article
(This article belongs to the Special Issue Stem Cell Activation in Adult Organism 2.0)
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Review
Non-Coding RNAs in Stem Cell Regulation and Cardiac Regeneration: Current Problems and Future Perspectives
Int. J. Mol. Sci. 2021, 22(17), 9160; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22179160 - 25 Aug 2021
Viewed by 466
Abstract
Although advances in rapid revascularization strategies following acute myocardial infarction (AMI) have led to improved short and long-term outcomes, the associated loss of cardiomyocytes and the subsequent remodeling result in an impaired ventricular function that can lead to heart failure or death. The [...] Read more.
Although advances in rapid revascularization strategies following acute myocardial infarction (AMI) have led to improved short and long-term outcomes, the associated loss of cardiomyocytes and the subsequent remodeling result in an impaired ventricular function that can lead to heart failure or death. The poor regenerative capacity of the myocardium and the current lack of effective regenerative therapies have driven stem cell research in search of a possible solution. One approach involves the delivery of stem cells to the site of injury in order to stimulate repair response. Although animal studies initially delivered promising results, the application of similar techniques in humans has been hampered by poor target site retention and oncogenic considerations. In response, several alternative strategies, including the use of non-coding RNAs (ncRNAs), have been introduced with the aim of activating and regulating stem cells or inducing stem cell status in resident cells. Circular RNAs (circRNAs) and microRNAs (miRNAs) are ncRNAs with pivotal functions in cell proliferation and differentiation, whose role in stem cell regulation and potential significance for the field of cardiac regeneration is the primary focus of this review. We also address the general advantages of ncRNAs as promising drivers of cardiac regeneration and potent stem cell regulators. Full article
(This article belongs to the Special Issue Stem Cell Activation in Adult Organism 2.0)
Review
Potential of Mesenchymal Stem Cells in the Rejuvenation of the Aging Immune System
Int. J. Mol. Sci. 2021, 22(11), 5749; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22115749 - 27 May 2021
Cited by 2 | Viewed by 1793
Abstract
Rapid growth of the geriatric population has been made possible with advancements in pharmaceutical and health sciences. Hence, age-associated diseases are becoming more common. Aging encompasses deterioration of the immune system, known as immunosenescence. Dysregulation of the immune cell production, differentiation, and functioning [...] Read more.
Rapid growth of the geriatric population has been made possible with advancements in pharmaceutical and health sciences. Hence, age-associated diseases are becoming more common. Aging encompasses deterioration of the immune system, known as immunosenescence. Dysregulation of the immune cell production, differentiation, and functioning lead to a chronic subclinical inflammatory state termed inflammaging. The hallmarks of the aging immune system are decreased naïve cells, increased memory cells, and increased serum levels of pro-inflammatory cytokines. Mesenchymal stem cell (MSC) transplantation is a promising solution to halt immunosenescence as the cells have excellent immunomodulatory functions and low immunogenicity. This review compiles the present knowledge of the causes and changes of the aging immune system and the potential of MSC transplantation as a regenerative therapy for immunosenescence. Full article
(This article belongs to the Special Issue Stem Cell Activation in Adult Organism 2.0)
Review
Energy Metabolism Plays a Critical Role in Stem Cell Maintenance and Differentiation
Int. J. Mol. Sci. 2016, 17(2), 253; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms17020253 - 18 Feb 2016
Cited by 56 | Viewed by 4486
Abstract
Various stem cells gradually turned to be critical players in tissue engineering and regenerative medicine therapies. Current evidence has demonstrated that in addition to growth factors and the extracellular matrix, multiple metabolic pathways definitively provide important signals for stem cell self-renewal and differentiation. [...] Read more.
Various stem cells gradually turned to be critical players in tissue engineering and regenerative medicine therapies. Current evidence has demonstrated that in addition to growth factors and the extracellular matrix, multiple metabolic pathways definitively provide important signals for stem cell self-renewal and differentiation. In this review, we mainly focus on a detailed overview of stem cell metabolism in vitro. In stem cell metabolic biology, the dynamic balance of each type of stem cell can vary according to the properties of each cell type, and they share some common points. Clearly defining the metabolic flux alterations in stem cells may help to shed light on stemness features and differentiation pathways that control the fate of stem cells. Full article
(This article belongs to the Special Issue Stem Cell Activation in Adult Organism)
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Review
Role of Epigenetics in Stem Cell Proliferation and Differentiation: Implications for Treating Neurodegenerative Diseases
Int. J. Mol. Sci. 2016, 17(2), 199; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms17020199 - 02 Feb 2016
Cited by 29 | Viewed by 4225
Abstract
The main objectives of this review are to survey the current literature on the role of epigenetics in determining the fate of stem cells and to assess how this information can be used to enhance the treatment strategies for some neurodegenerative disorders, like [...] Read more.
The main objectives of this review are to survey the current literature on the role of epigenetics in determining the fate of stem cells and to assess how this information can be used to enhance the treatment strategies for some neurodegenerative disorders, like Huntington’s disease, Parkinson’s disease and Alzheimer’s disease. Some of these epigenetic mechanisms include DNA methylation and histone modifications, which have a direct impact on the way that genes are expressed in stem cells and how they drive these cells into a mature lineage. Understanding how the stem cells are behaving and giving rise to mature cells can be used to inform researchers on effective ways to design stem cell-based treatments. In this review article, the way in which the basic understanding of how manipulating this process can be utilized to treat certain neurological diseases will be presented. Different genetic factors and their epigenetic changes during reprogramming of stem cells into induced pluripotent stem cells (iPSCs) have significant potential for enhancing the efficacy of cell replacement therapies. Full article
(This article belongs to the Special Issue Stem Cell Activation in Adult Organism)
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Review
Lung Regeneration: Endogenous and Exogenous Stem Cell Mediated Therapeutic Approaches
Int. J. Mol. Sci. 2016, 17(1), 128; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms17010128 - 19 Jan 2016
Cited by 44 | Viewed by 6055
Abstract
The tissue turnover of unperturbed adult lung is remarkably slow. However, after injury or insult, a specialised group of facultative lung progenitors become activated to replenish damaged tissue through a reparative process called regeneration. Disruption in this process results in healing by fibrosis [...] Read more.
The tissue turnover of unperturbed adult lung is remarkably slow. However, after injury or insult, a specialised group of facultative lung progenitors become activated to replenish damaged tissue through a reparative process called regeneration. Disruption in this process results in healing by fibrosis causing aberrant lung remodelling and organ dysfunction. Post-insult failure of regeneration leads to various incurable lung diseases including chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis. Therefore, identification of true endogenous lung progenitors/stem cells, and their regenerative pathway are crucial for next-generation therapeutic development. Recent studies provide exciting and novel insights into postnatal lung development and post-injury lung regeneration by native lung progenitors. Furthermore, exogenous application of bone marrow stem cells, embryonic stem cells and inducible pluripotent stem cells (iPSC) show evidences of their regenerative capacity in the repair of injured and diseased lungs. With the advent of modern tissue engineering techniques, whole lung regeneration in the lab using de-cellularised tissue scaffold and stem cells is now becoming reality. In this review, we will highlight the advancement of our understanding in lung regeneration and development of stem cell mediated therapeutic strategies in combating incurable lung diseases. Full article
(This article belongs to the Special Issue Stem Cell Activation in Adult Organism)
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Review
Regulatory System for Stem/Progenitor Cell Niches in the Adult Rodent Pituitary
Int. J. Mol. Sci. 2016, 17(1), 75; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms17010075 - 09 Jan 2016
Cited by 19 | Viewed by 2889
Abstract
The anterior lobe of the pituitary gland is a master endocrine tissue composed of five types of endocrine cells. Although the turnover rate of pituitary endocrine cells is as low as about 1.6% per day, recent studies have demonstrated that Sex-determining region Y-box [...] Read more.
The anterior lobe of the pituitary gland is a master endocrine tissue composed of five types of endocrine cells. Although the turnover rate of pituitary endocrine cells is as low as about 1.6% per day, recent studies have demonstrated that Sex-determining region Y-box 2 (SOX2)+-cells exist as pituitary stem/progenitor cells in the adult anterior lobe and contribute to cell regeneration. Notably, SOX2+-pituitary stem/progenitor cells form two types of niches in this tissue: the marginal cell layer (MCL-niche) and the dense cell clusters scattering in the parenchyma (parenchymal-niche). However, little is known about the mechanisms and factors for regulating the pituitary stem/progenitor cell niches, as well as the functional differences between the two types of niches. Elucidation of the regulatory mechanisms in the niches might enable us to understand the cell regeneration system that acts in accordance with physiological demands in the adult pituitary. In this review, so as to reveal the regulatory mechanisms of the two types of niche, we summarize the regulatory factors and their roles in the adult rodent pituitary niches by focusing on three components: soluble factors, cell surface proteins and extracellular matrixes. Full article
(This article belongs to the Special Issue Stem Cell Activation in Adult Organism)
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Review
Tissue Regeneration in the Chronically Inflamed Tumor Environment: Implications for Cell Fusion Driven Tumor Progression and Therapy Resistant Tumor Hybrid Cells
Int. J. Mol. Sci. 2015, 16(12), 30362-30381; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms161226240 - 19 Dec 2015
Cited by 22 | Viewed by 4150
Abstract
The biological phenomenon of cell fusion in a cancer context is still a matter of controversial debates. Even though a plethora of in vitro and in vivo data have been published in the past decades the ultimate proof that tumor hybrid cells could [...] Read more.
The biological phenomenon of cell fusion in a cancer context is still a matter of controversial debates. Even though a plethora of in vitro and in vivo data have been published in the past decades the ultimate proof that tumor hybrid cells could originate in (human) cancers and could contribute to the progression of the disease is still missing, suggesting that the cell fusion hypothesis is rather fiction than fact. However, is the lack of this ultimate proof a valid argument against this hypothesis, particularly if one has to consider that appropriate markers do not (yet) exist, thus making it virtually impossible to identify a human tumor cell clearly as a tumor hybrid cell. In the present review, we will summarize the evidence supporting the cell fusion in cancer concept. Moreover, we will refine the cell fusion hypothesis by providing evidence that cell fusion is a potent inducer of aneuploidy, genomic instability and, most likely, even chromothripsis, suggesting that cell fusion, like mutations and aneuploidy, might be an inducer of a mutator phenotype. Finally, we will show that “accidental” tissue repair processes during cancer therapy could lead to the origin of therapy resistant cancer hybrid stem cells. Full article
(This article belongs to the Special Issue Stem Cell Activation in Adult Organism)
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Review
Therapeutic Potential of Differentiated Mesenchymal Stem Cells for Treatment of Osteoarthritis
Int. J. Mol. Sci. 2015, 16(7), 14961-14978; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms160714961 - 02 Jul 2015
Cited by 45 | Viewed by 4631
Abstract
Osteoarthritis (OA) is a chronic, progressive, and irreversible degenerative joint disease. Conventional OA treatments often result in complications such as pain and limited activity. However, transplantation of mesenchymal stem cells (MSCs) has several beneficial effects such as paracrine effects, anti-inflammatory activity, and immunomodulatory [...] Read more.
Osteoarthritis (OA) is a chronic, progressive, and irreversible degenerative joint disease. Conventional OA treatments often result in complications such as pain and limited activity. However, transplantation of mesenchymal stem cells (MSCs) has several beneficial effects such as paracrine effects, anti-inflammatory activity, and immunomodulatory capacity. In addition, MSCs can be differentiated into several cell types, including chondrocytes, osteocytes, endothelia, and adipocytes. Thus, transplantation of MSCs is a suggested therapeutic tool for treatment of OA. However, transplanted naïve MSCs can cause problems such as heterogeneous populations including differentiated MSCs and undifferentiated cells. To overcome this problem, new strategies for inducing differentiation of MSCs are needed. One possibility is the application of microRNA (miRNA) and small molecules, which regulate multiple molecular pathways and cellular processes such as differentiation. Here, we provide insight into possible strategies for cartilage regeneration by transplantation of differentiated MSCs to treat OA patients. Full article
(This article belongs to the Special Issue Stem Cell Activation in Adult Organism)
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