MSC-Induced T-reg proliferation as a potential therapy for Multiple Sclerosis

Caleb Ellis

Introduction. Multiple Sclerosis (MS) is an autoimmune demyelinating disorder of the central nervous system that leads to progressively worsening and permanent neurological defects.1 MS is characterized by the activation of aberrant T-cells which then recognize and destroy myelinated neurons and oligodendrocytes, causing a massive inflammatory event and permanent neurological symptoms.1, 2 Current treatment options all hinge upon symptomatic management of the disease, however, mesenchymal stem cells have emerged as potential candidates for regenerative therapy for MS.1 MSCs have been shown to have an immunosuppressive effect by inhibiting inflammatory T-cells and inducing anti-inflammatory T-regulatory cells.3 Specifically, MSCs are known to influence the differentiation of these inflammatory and regulatory T-cells by secreted soluble factors and direct cell-to-cell contact.3,4 These findings all suggest a therapeutic potential for MSCs to mitigate the progression of MS. Methods. The majority of studies investigating the therapeutic potential of MSCs in autoimmune disease consist of in-vitro studies at a laboratory bench. These studies will soon transition to in-vivo models, and some already have, however this project focused on the mechanistic therapeutic action of MSCs in-vitro. Transwell co-culturing techniques were used to distinguish differences between soluble factors and direct cell-to-cell contact.3,5,7 Other studies have progressed to test the therapeutic potential of MSCs in the experimental autoimmune encephalitis (EAE) model in mice with promising results.2 Freud’s adjuvant is the preferred preparation to induce EAE.2 Results. Human MSCs have been shown to ultimately secrete TGF-β1 and CCL18 into the microenvironment to skew differentiation of naïve T-cells into CD4+CD25+FOX3P regulatory T cells.3 Indirect skewing of monocytes into Type II anti-inflammatory macrophages by secretion of M-CSF and CCL18 played a key role in the induction of T-regs.3 MSC expression of ICOS ligand was critical for cell-to-cell contact induced T-reg differentiation.7 Release of the proinflammatory cytokine IL-1β activates MSC expression of ICOSL, spurring contact with naïve T-cell ICOS receptors, thus activating the phosphoinositine-3-kinase-AKT pathway which ultimately yields gene products that promote T-reg proliferation.7 Conclusions. MSCs have long been known to possess potential as therapeutic agents for autoimmune and inflammatory disease mediated by the innate and adaptive immune systems.4,8 Many studies have yielded collaborating results that elucidate the mechanisms by which MSCs enact this immunomodulatory effect, primarily, through secreted mediators and direct cell-to-cell contact.4,7,9 As studies progress to in-vivo trials in animal and human models, MSCs hold promising potential as a therapeutic agent to combat the complex pathogenesis of MS.

  1. Juan Xiao, Rongbing Yang, Sangita Biswas, Xin Qin, Min Zhang and Wenbin Deng. Mesenchymal Stem Cells and Induced Pluripotent Stem Cells as Therapies for Multiple Sclerosis. Int. J. Mol. Sci. 2015, 16.
  2. Jiang H, Zhang Y, Tian K, Wang B, Han S. Amelioration of experimental autoimmune encephalomyelitis through transplantation of placental derived mesenchymal stem cells. Sci Rep. 2017;7:41837. doi: 10.1038/srep41837.
  3. Melief SM, et al. Multipotent stromal cells induce human regulatory T cells through a novel pathway involving skewing of monocytes toward anti-inflammatory macrophages. Stem Cells. 2013;31:1980–1991. doi: 10.1002/stem.1432.
  4. Gao F, Chiu SM, Motan DAL, Zhang Z, Chen L, Ji HL, et al. Mesenchymal stem cells and immunomodulation: current status and future prospects. Cell Death Dis. 2016;7:e2062. doi:10.1038/cddis.2015.327
  5. Luz-Crawford P, Kurte M, Bravo-Alegría J, Contreras R. Mesenchymal stem cells generate a CD4 + CD25 + Foxp3+ regulatory T cell population during the differentiation process of Th1 and Th17 cells. Stem Cell Res Ther. 2013;4(3):65. doi: 10.1186/scrt216.
  6. Miyagawa I, Nakayamada S, Nakano K, Yamagata K, Sakata K, Yamaoka K, et al.. Induction of regulatory T cells and its regulation with insulin-like growth factor/insulin-like growth factor binding protein-4 by human mesenchymal stem cells. J Immunol. (2017) 199:1616–25.
  7. Lee HJ, Kim SN, Jeon MS, Yi T, Song SU. ICOSL expression in human bone marrow-derived mesenchymal stem cells promotes induction of regulatory T cells. Sci Rep. (2017) 7:44486.
  8. Obermajer N., Popp F. C., Soeder Y., et al. Conversion of Th17 into IL-17A(neg) regulatory T cells: a novel mechanism in prolonged allograft survival promoted by mesenchymal stem cell-supported minimized immunosuppressive therapy. Journal of Immunology. 2014;193(10):4988–4999. doi: 10.4049/jimmunol.1401776.
  9. Mónica Kurte, Patricia Luz-Crawford, Ana María Vega-Letter, et. al.. IL17/IL17RA as a novel signaling axis Driving Mesenchymal stem cell Therapeutic Function in experimental autoimmune encephalomyelitis. Front Immunol. 2018; 9: 802.