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15 pages, 2514 KiB

Open AccessArticle

Impact of Janus Kinase Inhibition with Tofacitinib on Fundamental Processes of Bone Healing

by Timo Gaber, Antonia Clara Katharina Brinkman, Justyna Pienczikowski, Karoline Diesing, Alexandra Damerau, Moritz Pfeiffenberger, Annemarie Lang, Sarah Ohrndorf, Gerd-Rüdiger Burmester, Frank Buttgereit and Paula Hoff

Int. J. Mol. Sci. 2020, 21(3), 865; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21030865 - 29 Jan 2020

Cited by 20 | Viewed by 3321

Abstract

Both inflammatory diseases like rheumatoid arthritis (RA) and anti-inflammatory treatment of RA with glucocorticoids (GCs) or non-steroidal anti-inflammatory drugs (NSAIDs) negatively influence bone metabolism and fracture healing. Janus kinase (JAK) inhibition with tofacitinib has been demonstrated to act as a potent anti-inflammatory therapeutic [...] Read more.

Both inflammatory diseases like rheumatoid arthritis (RA) and anti-inflammatory treatment of RA with glucocorticoids (GCs) or non-steroidal anti-inflammatory drugs (NSAIDs) negatively influence bone metabolism and fracture healing. Janus kinase (JAK) inhibition with tofacitinib has been demonstrated to act as a potent anti-inflammatory therapeutic agent in the treatment of RA, but its impact on the fundamental processes of bone regeneration is currently controversially discussed and at least in part elusive. Therefore, in this study, we aimed to examine the effects of tofacitinib on processes of bone healing focusing on recruitment of human mesenchymal stromal cells (hMSCs) into the inflammatory microenvironment of the fracture gap, chondrogenesis, osteogenesis and osteoclastogenesis. We performed our analyses under conditions of reduced oxygen availability in order to mimic the in vivo situation of the fracture gap most optimal. We demonstrate that tofacitinib dose-dependently promotes the recruitment of hMSCs under hypoxia but inhibits recruitment of hMSCs under normoxia. With regard to the chondrogenic differentiation of hMSCs, we demonstrate that tofacitinib does not inhibit survival at therapeutically relevant doses of 10–100 nM. Moreover, tofacitinib dose-dependently enhances osteogenic differentiation of hMSCs and reduces osteoclast differentiation and activity. We conclude from our data that tofacitinib may influence bone healing by promotion of hMSC recruitment into the hypoxic microenvironment of the fracture gap but does not interfere with the cartilaginous phase of the soft callus phase of fracture healing process. We assume that tofacitinib may promote bone formation and reduce bone resorption, which could in part explain the positive impact of tofacitinib on bone erosions in RA. Thus, we hypothesize that it will be unnecessary to stop this medication in case of fracture and suggest that positive effects on osteoporosis are likely. Full article

(This article belongs to the Special Issue Recent Advances in Mesenchymal Stem Cell Immunomodulation and Regenerative Medicine)

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14 pages, 2924 KiB

Open AccessArticle

The Effects of Different Dynamic Culture Systems on Cell Proliferation and Osteogenic Differentiation in Human Mesenchymal Stem Cells

by Hsiou-Hsin Tsai, Kai-Chiang Yang, Meng-Huang Wu, Jung-Chih Chen and Ching-Li Tseng

Int. J. Mol. Sci. 2019, 20(16), 4024; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20164024 - 17 Aug 2019

Cited by 25 | Viewed by 4349

Abstract

The culture environment plays an important role for stem cells’ cultivation. Static or dynamic culture preserve differential potentials to affect human mesenchymal stem cells’ (hMSCs) proliferation and differentiation. In this study, hMSCs were seeded on fiber disks and cultured in a bidirectional-flow bioreactor [...] Read more.

The culture environment plays an important role for stem cells’ cultivation. Static or dynamic culture preserve differential potentials to affect human mesenchymal stem cells’ (hMSCs) proliferation and differentiation. In this study, hMSCs were seeded on fiber disks and cultured in a bidirectional-flow bioreactor or spinner-flask bioreactor with a supplement of osteogenic medium. The hMSCs’ proliferation, osteogenic differentiation, and extracellular matrix deposition of mineralization were demonstrated. The results showed that the spinner flask improved cell viability at the first two weeks while the bidirectional-flow reactor increased the cell proliferation of hMSCs through the four-week culture period. Despite the flow reactor having a higher cell number, a lower lactose/glucose ratio was noted, revealing that the bidirectional-flow bioreactor provides better oxygen accessibility to the cultured cells/disk construct. The changes of calcium ions in the medium, the depositions of Ca²⁺ in the cells/disk constructs, and alkaline phosphate/osteocalcin activities showed the static culture of hMSCs caused cells to mineralize faster than the other two bioreactors but without cell proliferation. Otherwise, cells were distributed uniformly with abundant extracellular matrix productions using the flow reactor. This reveals that the static and dynamic cultivations regulated the osteogenic process differently in hMSCs. The bidirectional-flow bioreactor can be used in the mass production and cultivation of hMSCs for applications in bone regenerative medicine. Full article

(This article belongs to the Special Issue Recent Advances in Mesenchymal Stem Cell Immunomodulation and Regenerative Medicine)

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23 pages, 5567 KiB

Open AccessArticle

Enhanced Hepatogenic Differentiation of Human Wharton’s Jelly–Derived Mesenchymal Stem Cells by Using Three-Step Protocol

by Wachira Panta, Sumeth Imsoonthornruksa, Ton Yoisungnern, Sanong Suksaweang, Mariena Ketudat-Cairns and Rangsun Parnpai

Int. J. Mol. Sci. 2019, 20(12), 3016; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20123016 - 20 Jun 2019

Cited by 10 | Viewed by 3759

Abstract

Currently, human Wharton’s jelly-derived mesenchymal stem cells (hWJ-MSCs) are an attractive source of stem cells for cell-based therapy, owing to their ability to undergo self-renewal and differentiate into all mesodermal, some neuroectodermal, and endodermal progenies, including hepatocytes. Herein, this study aimed to investigate [...] Read more.

Currently, human Wharton’s jelly-derived mesenchymal stem cells (hWJ-MSCs) are an attractive source of stem cells for cell-based therapy, owing to their ability to undergo self-renewal and differentiate into all mesodermal, some neuroectodermal, and endodermal progenies, including hepatocytes. Herein, this study aimed to investigate the effects of sodium butyrate (NaBu), an epigenetic regulator that directly inhibits histone deacetylase, on hepatic endodermal lineage differentiation of hWJ-MSCs. NaBu, at 1 mM, optimally promoted endodermal differentiation of hWJ-MSCs, along with epidermal growth factor (EGF) and basic fibroblast growth factor (bFGF) supplementation. CXCR4, HNF3β, SOX17 (endodermal), and GATA6 (mesendodermal) mRNAs were also up-regulated (p < 0.001). Immunocytochemistry and a Western blot analysis of SOX17 and HNF3β confirmed that the 1 mM NaBu along with EGF and bFGF supplementation condition was appropriately pre-treated with hWJ-MSCs before hepatogenic differentiation. Furthermore, the hepatic differentiation medium with NaBu pre-treatment up-regulated hepatoblast (AFP and HNF3β) and hepatic (CK18 and ALB) markers, and increased the proportion of mature hepatocyte functions, including G6P, C/EBPα, and CYP2B6 mRNAs, glycogen storage and urea secretion. The hepatic differentiation medium with NaBu in the pre-treatment step can induce hWJ-MSC differentiation toward endodermal, hepatoblastic, and hepatic lineages. Therefore, the hepatic differentiation medium with NaBu pre-treatment for differentiating hWJ-MSCs could represent an alternative protocol for cell-based therapy and drug screening in clinical applications. Full article

(This article belongs to the Special Issue Recent Advances in Mesenchymal Stem Cell Immunomodulation and Regenerative Medicine)

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Review

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24 pages, 427 KiB

Open AccessReview

Osteoporosis and the Potential of Cell-Based Therapeutic Strategies

by Iratxe Macías, Natividad Alcorta-Sevillano, Clara I. Rodríguez and Arantza Infante

Int. J. Mol. Sci. 2020, 21(5), 1653; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21051653 - 28 Feb 2020

Cited by 52 | Viewed by 4502

Abstract

Osteoporosis, the most common chronic metabolic bone disease, is characterized by low bone mass and increased bone fragility. Nowadays more than 200 million individuals are suffering from osteoporosis and still the number of affected people is dramatically increasing due to an aging population [...] Read more.

Osteoporosis, the most common chronic metabolic bone disease, is characterized by low bone mass and increased bone fragility. Nowadays more than 200 million individuals are suffering from osteoporosis and still the number of affected people is dramatically increasing due to an aging population and longer life, representing a major public health problem. Current osteoporosis treatments are mainly designed to decrease bone resorption, presenting serious adverse effects that limit their safety for long-term use. Numerous studies with mesenchymal stem cells (MSCs) have helped to increase the knowledge regarding the mechanisms that underlie the progression of osteoporosis. Emerging clinical and molecular evidence suggests that inflammation exerts a significant influence on bone turnover, thereby on osteoporosis. In this regard, MSCs have proven to possess broad immunoregulatory capabilities, modulating both adaptive and innate immunity. Here, we will discuss the role that MSCs play in the etiopathology of osteoporosis and their potential use for the treatment of this disease. Full article

(This article belongs to the Special Issue Recent Advances in Mesenchymal Stem Cell Immunomodulation and Regenerative Medicine)

14 pages, 934 KiB

Open AccessReview

Bone Control of Muscle Function

by Giulia Battafarano, Michela Rossi, Francesco Marampon, Salvatore Minisola and Andrea Del Fattore

Int. J. Mol. Sci. 2020, 21(4), 1178; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21041178 - 11 Feb 2020

Cited by 33 | Viewed by 5929

Abstract

Bone and muscle represent a single functional system and are tightly connected to each other. Indeed, diseases characterized by alterations of muscle physiology have effects on bone remodeling and structure and vice versa. Muscle influence on bone has been deeply studied, and recent [...] Read more.

Bone and muscle represent a single functional system and are tightly connected to each other. Indeed, diseases characterized by alterations of muscle physiology have effects on bone remodeling and structure and vice versa. Muscle influence on bone has been deeply studied, and recent studies identified irisin as new molecule involved in this crosstalk. Muscle regulation by bone needs to be extensively investigated since in the last few years osteocalcin was recognized as a key molecule in the bone–muscle interaction. Osteocalcin can exist in two forms with different degrees of carboxylation. The undercarboxylated form of osteocalcin is a hormone released by the bone matrix during the osteoclast bone resorption and can bind its G-protein coupled receptor GPRC6A expressed in the muscle, thus regulating its function. Recently, this hormone was described as an antiaging molecule for its ability to regulate bone, muscle and cognitive functions. Indeed, the features of this bone-related hormone were used to test a new therapeutic approach for sarcopenia, since injection of osteocalcin in older mice induces the acquirement of physical abilities of younger animals. Even if this approach should be tested in humans, osteocalcin represents the most surprising molecule in endocrine regulation by the skeleton. Full article

(This article belongs to the Special Issue Recent Advances in Mesenchymal Stem Cell Immunomodulation and Regenerative Medicine)

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21 pages, 1032 KiB

Open AccessReview

Immunomodulatory and Regenerative Effects of Mesenchymal Stem Cell-Derived Extracellular Vesicles in Renal Diseases

by Kenji Tsuji, Shinji Kitamura and Jun Wada

Int. J. Mol. Sci. 2020, 21(3), 756; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21030756 - 23 Jan 2020

Cited by 28 | Viewed by 4170

Abstract

Mesenchymal stem cells (MSCs) have immunomodulatory and regenerative effects in many organs, including the kidney. Emerging evidence has shown that the trophic effects from MSCs are mainly mediated by the paracrine mechanism rather than the direct differentiation of MSCs into injured tissues. These [...] Read more.

Mesenchymal stem cells (MSCs) have immunomodulatory and regenerative effects in many organs, including the kidney. Emerging evidence has shown that the trophic effects from MSCs are mainly mediated by the paracrine mechanism rather than the direct differentiation of MSCs into injured tissues. These secretomes from MSCs include cytokines, growth factors, chemokines and extracellular vesicles (EVs) containing microRNAs, mRNAs, and proteins. Many research studies have revealed that secretomes from MSCs have potential to ameliorate renal injury in renal disease models, including acute kidney injury and chronic kidney disease through a variety of mechanisms. These trophic mechanisms include immunomodulatory and regenerative effects. In addition, accumulating evidence has uncovered the specific factors and therapeutic mechanisms in MSC-derived EVs. In this article, we summarize the recent advances of immunomodulatory and regenerative effects of EVs from MSCs, especially focusing on the microRNAs. Full article

(This article belongs to the Special Issue Recent Advances in Mesenchymal Stem Cell Immunomodulation and Regenerative Medicine)

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17 pages, 862 KiB

Open AccessReview

Immunomodulatory Effects of MSCs in Bone Healing

by Dalia Medhat, Clara I. Rodríguez and Arantza Infante

Int. J. Mol. Sci. 2019, 20(21), 5467; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20215467 - 02 Nov 2019

Cited by 63 | Viewed by 6456

Abstract

Mesenchymal stem cells (MSCs) are capable of differentiating into multilineage cells, thus making them a significant prospect as a cell source for regenerative therapy; however, the differentiation capacity of MSCs into osteoblasts seems to not be the main mechanism responsible for the benefits [...] Read more.

Mesenchymal stem cells (MSCs) are capable of differentiating into multilineage cells, thus making them a significant prospect as a cell source for regenerative therapy; however, the differentiation capacity of MSCs into osteoblasts seems to not be the main mechanism responsible for the benefits associated with human mesenchymal stem cells hMSCs when used in cell therapy approaches. The process of bone fracture restoration starts with an instant inflammatory reaction, as the innate immune system responds with cytokines that enhance and activate many cell types, including MSCs, at the site of the injury. In this review, we address the influence of MSCs on the immune system in fracture repair and osteogenesis. This paradigm offers a means of distinguishing target bone diseases to be treated with MSC therapy to enhance bone repair by targeting the crosstalk between MSCs and the immune system. Full article

(This article belongs to the Special Issue Recent Advances in Mesenchymal Stem Cell Immunomodulation and Regenerative Medicine)

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13 pages, 1496 KiB

Open AccessReview

The Role of Growth Hormone in Mesenchymal Stem Cell Commitment

by Simona Bolamperti, Francesca Guidobono, Alessandro Rubinacci and Isabella Villa

Int. J. Mol. Sci. 2019, 20(21), 5264; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20215264 - 23 Oct 2019

Cited by 10 | Viewed by 4455

Abstract

Growth hormone (GH) is best known for its prominent role in promoting prepubertal growth and in regulating body composition and metabolism during adulthood. In recent years, the possible role of GH in the modulation of mesenchymal stem cell (MSC) commitment has gained interest. [...] Read more.

Growth hormone (GH) is best known for its prominent role in promoting prepubertal growth and in regulating body composition and metabolism during adulthood. In recent years, the possible role of GH in the modulation of mesenchymal stem cell (MSC) commitment has gained interest. MSCs, characterized by active self-renewal and differentiation potential, express GH receptors. In MSCs derived from different adult tissues, GH induces an inhibition of adipogenic differentiation and favors MSC differentiation towards osteogenesis. This activity of GH indicates that regulation of body composition by GH has already started in the tissue progenitor cells. These findings have fostered research on possible uses of MSCs treated with GH in those pathologies, where a lack of or delays in bone repair occur. After an overview of GH activities, this review will focus on the research that has characterized GH’s effects on MSCs and on preliminary studies on the possible application of GH in bone regenerative medicine. Full article

(This article belongs to the Special Issue Recent Advances in Mesenchymal Stem Cell Immunomodulation and Regenerative Medicine)

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22 pages, 374 KiB

Open AccessReview

Insights into the Secretome of Mesenchymal Stem Cells and Its Potential Applications

by Sharon Eleuteri and Alessandra Fierabracci

Int. J. Mol. Sci. 2019, 20(18), 4597; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20184597 - 17 Sep 2019

Cited by 181 | Viewed by 6543

Abstract

Mesenchymal stem cells (MSCs) have regenerative, immunoregulatory properties and can be easily isolated and expanded in vitro. Despite being a powerful tool for clinical applications, they present limitations in terms of delivery, safety, and variability of therapeutic response. Interestingly, the MSC secretome composed [...] Read more.

Mesenchymal stem cells (MSCs) have regenerative, immunoregulatory properties and can be easily isolated and expanded in vitro. Despite being a powerful tool for clinical applications, they present limitations in terms of delivery, safety, and variability of therapeutic response. Interestingly, the MSC secretome composed by cytokines, chemokines, growth factors, proteins, and extracellular vesicles, could represent a valid alternative to their use. It is noteworthy that MSC-derived extracellular vesicles (MSC-EVs) have the same effect and could be advantageous compared to the parental cells because of their specific miRNAs load. MiRNAs could be useful both in diagnostic procedures such as “liquid biopsy” to identify early pathologies and in the therapeutic field. Not only are MSC-EVs’ preservation, transfer, and production easier, but their administration is also safer, hence some clinical trials are ongoing. However, much effort is required to improve the characterization of EVs to avoid artifacts and guarantee reproducibility of the studies. Full article

(This article belongs to the Special Issue Recent Advances in Mesenchymal Stem Cell Immunomodulation and Regenerative Medicine)

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