Stem cells are cells specialized cell, capable of renewing themselves through cell division and can differentiate into multi-lineage cells. These cells are categorized as embryonic stem cells (ESCs), induced pluripotent stem cells (iPSCs) and adult stem cells. Mesenchymal stem cells (MSCs) are adult stem cells which can be isolated from human and animal sources. Human MSCs (hMSCs) are the non-haematopoietic, multipotent stem cells with the capacity to differentiate into mesodermal lineage such as osteocytes, adipocytes and chondrocytes as well ectodermal (neurocytes) and endodermal lineages (hepatocytes). MSCs express cell surface markers like cluster of differentiation (CD)29, CD44, CD73, CD90, CD105 and lack the expression of CD14, CD34, CD45 and HLA (human leucocyte antigen)-DR. hMSCs for the first time were reported in the bone marrow and till now they have been isolated from various tissues, including adipose tissue, amniotic fluid, endometrium, dental tissues, umbilical cord and Wharton's jelly which harbours potential MSCs. hMSCs have been cultured long-term in specific media without any severe abnormalities. Furthermore, MSCs have immunomodulatory features, secrete cytokines and immune-receptors which regulate the microenvironment in the host tissue. Multilineage potential, immunomodulation and secretion of anti-inflammatory molecules makes MSCs an effective tool in the treatment of chronic diseases. In the present review, we have highlighted recent research findings in the area of hMSCs sources, expression of cell surface markers, long-term in vitro culturing, in vitro differentiation potential, immunomodulatory features, its homing capacity, banking and cryopreservation, its application in the treatment of chronic diseases and its use in clinical trials.

Human mesenchymal stem cells - current trends and future prospective

The unique immunomodulatory properties of mesenchymal stem cells (MSCs) make them an invaluable cell type for the repair of tissue/ organ damage caused by chronic inflammation or autoimmune disorders. Although they hold great promise in the treatment of immune disorders such as graft versus host disease (GvHD) and allergic disorders, there remain many challenges to overcome before their widespread clinical application. An understanding of the biological properties of MSCs will clarify the mechanisms of MSC-based transplantation for immunomodulation. In this review, we summarize the preclinical and clinical studies of MSCs from different adult tissues, discuss the current hurdles to their use and propose the future development of pluripotent stem cell-derived MSCs as an approach to immunomodulation therapy.

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Mesenchymal stem cells and immunomodulation: current status and future prospects

Aside from the well-established self-renewal and multipotent differentiation properties, mesenchymal stem cells exhibit both immunomodulatory and anti-inflammatory roles in several experimental autoimmune and inflammatory diseases. In this study, we isolated a new population of stem cells from human gingiva, a tissue source easily accessible from the oral cavity, namely, gingiva-derived mesenchymal stem cells (GMSCs), which exhibited clonogenicity, self-renewal, and multipotent differentiation capacities. Most importantly, GMSCs were capable of immunomodulatory functions, specifically suppressed peripheral blood lymphocyte proliferation, induced expression of a wide panel of immunosuppressive factors including IL-10, IDO, inducible NO synthase (iNOS), and cyclooxygenase 2 (COX-2) in response to the inflammatory cytokine, IFN-γ. Cell-based therapy using systemic infusion of GMSCs in experimental colitis significantly ameliorated both clinical and histopathological severity of the colonic inflammation, restored the injured gastrointestinal mucosal tissues, reversed diarrhea and weight loss, and suppressed the overall disease activity in mice. The therapeutic effect of GMSCs was mediated, in part, by the suppression of inflammatory infiltrates and inflammatory cytokines/mediators and the increased infiltration of regulatory T cells and the expression of anti-inflammatory cytokine IL-10 at the colonic sites. Taken together, GMSCs can function as an immunomodulatory and anti-inflammatory component of the immune system in vivo and is a promising cell source for cell-based treatment in experimental inflammatory diseases.

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Mesenchymal stem cells derived from human gingiva are capable of immunomodulatory functions and ameliorate inflammation-related tissue destruction in experimental colitis

https://journals.sagepub.com/doi/pdf/10.3727/096368913X667709

Paracrine mechanisms of mesenchymal stem cell-based therapy: current status and perspectives.

Mesenchymal stem cells (MSCs; also referred to as mesenchymal stromal cells) have attracted much attention for their ability to regulate inflammatory processes. Their therapeutic potential is currently being investigated in various degenerative and inflammatory disorders such as Crohn’s disease, graft-versus-host disease, diabetic nephropathy and organ fibrosis. The mechanisms by which MSCs exert their therapeutic effects are multifaceted, but in general, these cells are thought to enable damaged tissues to form a balanced inflammatory and regenerative microenvironment in the presence of vigorous inflammation. Studies over the past few years have demonstrated that when exposed to an inflammatory environment, MSCs can orchestrate local and systemic innate and adaptive immune responses through the release of various mediators, including immunosuppressive molecules, growth factors, exosomes, chemokines, complement components and various metabolites. Interestingly, even nonviable MSCs can exert beneficial effects, with apoptotic MSCs showing immunosuppressive functions in vivo. Because the immunomodulatory capabilities of MSCs are not constitutive but rather are licensed by inflammatory cytokines, the net outcomes of MSC activation might vary depending on the levels and the types of inflammation within the residing tissues. Here, we review current understanding of the immunomodulatory mechanisms of MSCs and the issues related to their therapeutic applications.

Immunoregulatory mechanisms of mesenchymal stem and stromal cells in inflammatory diseases.

Bone marrow-derived mesenchymal stem cells (BMSCs) are a widely researched adult stem cell population capable of differentiation into various lineages Because many promising applications of tissue engineering require cell expansion following harvest and involve the treatment of diseases and conditions found in an aging population, the effect of donor age and ex vivo handling must be understood in order to develop clinical techniques and therapeutics based on these cells Furthermore, there currently exists little understanding as to how these two factors may be influenced by one another Differences in the adipogenic, chondrogenic, and osteogenic differentiation capacity of murine MSCs harvested from donor animals of different age and number of passages of these cells were observed Cells from younger donors adhered to tissue culture polystyrene better and proliferated in greater number than those from older animals Chondrogenic and osteogenic potential decreased with age for each group, and adipogenic differentiation decreased only in cells from the oldest donors Significant decreases in differentiation potentials due to passage were observed as well for osteogenesis of BMSCs from the youngest donors and chondrogenesis of the cells from the oldest donors Both increasing age and the number of passages have lineage dependent effects on BMSC differentiation potential Furthermore, there is an obvious interplay between donor age and cell passage that in the future must be accounted for when developing cell-based therapies for clinical use

https://link.springer.com/content/pdf/10.1186%2F1471-2121-9-60.pdf

Donor age and cell passage affects differentiation potential of murine bone marrow-derived stem cells

Bone-marrow-derived mesenchymal stem cells (MSCs) have been shown to possess immunosuppressive properties, e.g., by inhibiting T cell proliferation. Activated T cells can also enhance the immunosuppression ability of MSCs. The precise mechanisms underlying MSC-mediated immunosuppression remain largely undefined, although both cell-cell contact and soluble factors have been implicated; nor is it clear how the immunosuppressive property of MSCs is modulated by T cells. Using MSCs isolated from mouse bone marrow, we show here that interferon gamma (IFNgamma), a well-known proinflammatory cytokine produced by activated T cells, plays an important role in priming the immunosuppressive property of MSCs. Mechanistically, IFNgamma acts directly on MSCs and leads to up-regulation of B7-H1, an inhibitory surface molecule in these stem cells. MSCs primed by activated T cells derived from IFNgamma-/- mouse exhibited dramatically reduced ability to suppress T cell proliferation, a defect that can be rescued by supplying exogenous IFNgamma. Moreover, siRNA-mediated knockdown of B7-H1 in MSCs abolished immunosuppression by these cells. Taken together, our results suggest that IFNgamma plays a critical role in triggering the immunosuppresion by MSCs through up-regulating B7-H1 in these cells, and provide evidence supporting the cell-cell contact mechanism in MSC-mediated immunosuppression.

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A critical role of IFNgamma in priming MSC-mediated suppression of T cell proliferation through up-regulation of B7-H1.

Schwann cells (SCs) in animals exist in different developmental stages or wound repair phases, distinguished mainly by the expression of SC-specific markers. No study has yet determined SC state under in vitro culture conditions, and the specific markers expressed in SC are obscure as well. In this study, we harvested sciatic nerves from newborn mice and isolated SCs by an enzyme-digestion method, then we examined the expression profiles of ten markers (S100, p75NTR, Sox10, Sox2, GAP43, NCAM, Krox20, Oct6, MBP, and MPZ) at both the RNA and protein levels in in vitro mouse SCs and speculated their relation with in vivo SC stages. We assayed RNA and protein levels of SC specific markers by immunofluorescence, Western Blot, and real-time quantitative RT-PCR. The results show that the expression of most markers (S100, p75NTR, GAP43, NCAM, Krox20, Oct6, MBP and MPZ) was not detectable in all of early stage cultured SCs. The expression of transcription factors Sox10 and Sox2 was, however, detectable in all SCs. After 8 days, the positive expression rate of all markers except GAP43 and Oct6 was almost 100%.These results indicates Sox10 is a necessary marker for SC identification, while S100 is not reliable. SCs cultured in vitro express Sox2, P75NTR, NCAM, GAP43, Oct6, and MPZ, suggesting that they are similar to in vivo undifferentiated iSCs or dedifferentiated iSCs after nerve injury.

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Yuqing Jin

Papers

Donor age and cell passage affects differentiation potential of murine bone marrow-derived stem cells

A critical role of IFNgamma in priming MSC-mediated suppression of T cell proliferation through up-regulation of B7-H1.

Specific Marker Expression and Cell State of Schwann Cells during Culture In Vitro

Cryopreservation of tissue-engineered epithelial sheets in trehalose.

Efficient Schwann cell purification by differential cell detachment using multiplex collagenase treatment.