Ecto-mesenchymal stem cells: a new player for immune regulation and cell therapy

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Extensive studies have demonstrated that mesenchymal stem cells (MSCs) are multipotent mesoderm-derived stromal cells that can differentiate into a variety of cell types, including adipocytes, osteoblasts, chondrocytes, myocytes and neuronal cells.1 MSCs are found in numerous organs and tissues, including bone marrow, heart, lung, muscle, peripheral blood, adipose tissue, cartilage, synovium, dental pulp, tonsil, umbilical cord, placenta, thymus and olfactory mucosa.1 MSCs have been shown to possess potent immunosuppressive functions and tissue repair capacities, which have facilitated the clinical applications of MSCs in treating a diverse range of disorders involving angiogenesis and fibrosis, including rheumatic diseases and graft-versus-host diseases.2, 3 Here, we provide a brief commentary on newly emerging evidence of the immunoregulatory function and potential application of ecto-mesenchymal stem cells.

IMMUNOREGULATORY FUNCTIONS OF ECTO-MESENCHYMAL STEM CELLS

Recent studies have identified a novel MSC subset in nasal lamina propria, namely, olfactory ecto-mesenchymal stem cells (OE-MSCs).4, 5 OE-MSCs can differentiate, similar to MSCs derived from other tissues or organs, yet OE-MSCs also display neurogenic capacity. Upon transplantation into mice with hippocampal lesions, human OE-MSCs can stimulate endogenous neurogenesis and promote synaptic transmission.6 Remarkably, OE-MSC-treated mice exhibit improved learning and memory capabilities in behavioral tests.6 Although both the tissue repair and regeneration capacity of OE-MSCs have been well studied, whether OE-MSCs also possess immunomodulatory function has remained largely unclear. Recently, we have characterized the functional features of OE-MSCs both in vitro and in vivo.7 Previous studies have suggested that immunoregulatory factors produced by MSCs, such as nitric oxide (NO), indoleamine 2,3-dioxygenase (IDO), programmed death-1 ligand (PD-L1) and interleukin-10 (IL-10), contribute to the formation of an immunosuppressive milieu.8 Consistent with these observations, we detected significantly higher PD-L1 expression and a stronger capacity of OE-MSCs to produce NO, IL-10 and TGF-β when compared with BM-derived MSCs (BM-MSCs).7 OE-MSCs show potent immunosuppressive function by inhibiting T cell proliferation in culture. Moreover, OE-MSCs markedly enhance regulatory T (Treg) cell differentiation from naive T cells. Notably, mice with collagen-induced arthritis (CIA) that are treated with OE-MSCs exhibit substantially ameliorated disease pathology with reduced serum levels of proinflammatory cytokines such as IFN-γ and IL-17. In addition, CIA mice treated with OE-MSCs show a significantly increased frequency of CD4+Foxp3+ Treg cells but reduced IFN-γ-producing Th1 and IL-17-producing Th17 cells. Altogether, these findings demonstrate the immunoregulatory function of OE-MSCs. Our recent studies have shown that umbilical cord-derived MSC transplantation increases Treg cells and reduces Th17 cells through the regulation of TGF-β and PGE2 in lupus patients.9, 10 This evidence supports the potential application of OE-MSCs in the treatment of autoimmune diseases and other disorders with immune dysregulations.

FUNCTIONAL MODULATIONS OF ECTO-MESENCHYMAL STEM CELLS

Accumulated data have suggested that inflammatory stimuli from a tissue’s microenvironment can reciprocally affect the functionality and plasticity of MSCs under conditions of infection, autoimmunity and cancer.8 There is also evidence indicating that immunosuppressive functions are not constitutively possessed by MSCs. Instead, local inflammatory factors may license MSCs to become immunosuppressive.11 Among many inflammatory cytokines and chemokines, IFN-γ is found to be essentially involved in eliciting the immunosuppressive functions of MSCs.12, 13 Elegant studies by Ren et al.14 have further demonstrated that the concomitant presence of other proinflammatory cytokines (TNF-α, IL-1α or IL-β) with IFN-γ are required to induce immunosuppression by MSCs through the concerted action of chemokines and NO. IL-17 has been identified as a key proinflammatory cytokine in the pathogenesis of various autoimmune diseases. Interestingly, Han et al.15 uncovered a synergistic effect of IL-17 to enhance the immunosuppressive function of BM-MSCs via enhancing the stability of iNOS-encoding transcripts mediated by the RNA-binding protein AUF1. However, our recent studies have revealed a novel function of IL-17 in attenuating the immunosuppressive capacities of OE-MSCs.16 Notably, IL-17-treated OE-MSCs show significantly compromised regulatory function in restraining CD4+ T cell expansion and fail to induce Treg cell differentiation in culture. Correspondingly, IL-17 treatment significantly downregulates the expression of iNOS, IL-10 and TGF-β in OE-MSCs. Moreover, adoptive transfer of IL-17-treated OE-MSCs results in no obvious or only mild amelioration of disease pathology in CIA mice. In addition, the immunosuppressive functions of OE-MSCs are restored in vivo when IL-17 receptor expression is knocked down in OE-MSCs. Interestingly, previous studies have identified a novel subpopulation of IL-17-producing MSCs, which exhibit no immunosuppressive functions and are not able to induce Treg cells or suppress Th17 cells.17 Furthermore, IL-17 has been found to inhibit TGF-β1 expression via activation of the NF-κB pathway in IL-17+ MSCs, whereas knockdown of IL-17 can restore the immunosuppressive functions of MSCs.17 Currently, it remains unclear whether all MSC subpopulations express IL-17 receptors and how MSCs are functionally modulated by IL-17 and other proinflammatory cytokines at different stages of an inflammatory response or tissue injury. It becomes clear that ligation of different Toll-like receptors (TLRs) on both murine and human MSCs has a crucial role in dictating both phenotypes and functions of MSCs under various disease conditions. It has also been recognized that the overall influence of various cytokines and TLR ligations may render MSCs to retain their immunosuppressive function or promote the inflammatory response by recruiting immune cells into the inflammatory milieu or damaged tissue microenvironment. Therefore, further studies are required to determine how microenvironmental factors modulate the functions of OE-MSCs.

POTENTIAL APPLICATION OF ECTO-MESENCHYMAL STEM CELLS FOR CELLULAR THERAPY

In recent years, the well-characterized capacities of tissue repair and immunomodulation of MSCs have prompted researchers to conduct cell therapies for treating various types of disease. As of June 2017, there are 249 open studies registered for MSC clinical trials (http://www.clinicaltrials.gov). Although BM has been well-established as the primary source for harvesting MSCs, intensive efforts have been made to search for alternative sources of MSCs derived from other tissues due to the invasive nature of BM aspiration. A recent clinical trial using adipose-derived MSCs has shown beneficial effects in patients with rheumatoid arthritis.18 As a novel MSC subset, OE-MSCs are broadly distributed within the lamina propria of the superior, middle and inferior turbinates in the nasal cavity. Thus, OE-MSCs are easily accessible for sample harvest and can be rapidly expanded in culture.19 Current studies indicate that OE-MSC engraftment is well tolerated and highly competent with immunomodulatory functions for treating neural tissue injuries and autoimmune arthritis in animal models. Despite their similar or even identical phenotypes, MSCs derived from different tissues have been shown to elicit variable therapeutic effects owing to their unique genetic signatures, migratory capacities, isolation methods and passage times upon adoptive transfer.20, 21 Although rapid advances have been achieved in utilizing MSCs as an effective cellular therapy in clinical applications, several studies have reported that MSC-based therapies fail to reach the primary endpoints.22, 23 Thus, further investigations are needed to unveil the mechanistic network that functionally shapes MSC activities and to optimize the clinical protocol of MSC therapy for future treatment, which will contribute to the validation of OE-MSCs as a new candidate for cell therapy.24

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Acknowledgements

This study was supported by grants from the Natural Science Foundation of Jiangsu (BK20170563), National Natural Science Foundation of China (No. 81373195), National Basic Research Program of China (2014CB541904) and Natural Science Foundation of Jiangsu (BK20150533).

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Correspondence to Shengjun Wang or Liwei Lu.

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The authors declare no conflict of interest.

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