Human Wharton's Jelly-Derived Stem Cells Display Immunomodulatory Properties and Transiently Improve Rat Experimental Autoimmune Encephalomyelitis

Abstract

Umbilical cord matrix or Wharton's jelly-derived stromal cells (WJ-MSCs) are an easily accessible source of mesenchymal-like stem cells. Recent studies describe a hypoimmunogenic phenotype, multipotent differentiation potential, and trophic support function for WJ-MSCs, with variable clinical benefit in degenerative disease models such as stroke, myocardial infarction, and Parkinson's disease. It remains unclear whether WJ-MSCs have therapeutic value for multiple sclerosis (MS), where autoimmune-mediated demyelination and neurodegeneration need to be halted. In this study, we investigated whether WJ-MSCs possess the required properties to effectively and durably reverse these pathological hallmarks and whether they survive in an inflammatory environment after transplantation. WJ-MSCs displayed a lowly immunogenic phenotype and showed intrinsic expression of neurotrophic factors and a variety of anti-inflammatory molecules. Furthermore, they dose-dependently suppressed proliferation of activated T cells using contact-dependent and paracrine mechanisms. Indoleamine 2,3-dioxygenase 1 was identified as one of the main effector molecules responsible for the observed T-cell suppression. The immune-modulatory phenotype of WJ-MSCs was further enhanced after proinflammatory cytokine treatment in vitro (licensing). In addition to their effect on adaptive immunity, WJ-MSCs interfered with dendritic cell differentiation and maturation, thus directly affecting antigen presentation and therefore T-cell priming. Systemically infused WJ-MSCs potently but transiently ameliorated experimental autoimmune encephalomyelitis (EAE), an animal model for MS, when injected at onset or during chronic disease. This protective effect was paralleled with a reduction in autoantigen-induced T-cell proliferation, confirming their immunomodulatory activity in vivo. Surprisingly, in vitro licensed WJ-MSCs did not ameliorate EAE, indicative of a fast rejection as a result of enhanced immunogenicity. Collectively, we show that WJ-MSCs have trophic support properties and effectively modulate immune cell functioning both in vitro and in the EAE model, suggesting WJ-MSC may hold promise for MS therapy. Future research is needed to optimize survival of stem cells and enhance clinical durability.

Crosstalk with Inflammatory Macrophages Shapes the Regulatory Properties of Multipotent Adult Progenitor Cells

“…In line with this finding, we have previously found that IL-1 β increases COX-2 mRNA in rMAPC [25]. Overall, we conclude that these immunoregulatory mechanisms can be triggered by activated macrophages while collectively these observations confirm the notion that “licensing” of MAPC enhances their paracrine effects [25, 58, 61] and renders them as an ideal cell type for transplantation in neuroinflammatory conditions.…”

“…Therefore, it is of high importance to elucidate how MAPC modulate the features of myeloid cell types since intravenously transplanted cells are likely to be localized in close proximity with myeloid cells in the CNS and periphery [37, 61, 69]. Overall, we showed that inflammatory macrophages are able to regulate the immunomodulatory properties of rMAPC in vitro, thereby warranting confirmatory in vivo studies.…”

The transplantation of mesenchymal stem cells derived from unconventional sources: an innovative approach to multiple sclerosis therapy

“…These results were corroborated by a recent study of 2015 (Donders et al 2015) which showed that intravenous transplantation of allogenic WJ-MSCs (2 × 10 6 ) into EAE rats led to a reduction of autoantigen-induced T-cell proliferation through contact-dependent and paracrine mechanisms proving their immunomodulatory activity. Here, WJ-MSCs were also found to have a low immunogenic phenotype and show intrinsic expression of neurotrophic factors (BDNF, GDNF, and NGF) and anti-inflammatory molecule (IL-10).…”

“…The safety and efficacy of hUC-MSCs were also evaluated in the treatment of secondary progressive MS patients EAE amelioration Donders et al (2015) Human decidua Downregulation of IL-17 and RORγT, upregulation of IL-10, IL-4 and GATA-3…”

Therapeutic effects of adipose derived mesenchymal stem cells on remyelination process in inflammatory demyelinating diseases

“…In addition, wharton's jelly-derived stromal cells (WJ-MSC) implantation into EAE model of MS, have neuroprotective effects which were parallel with a reduction in autoantigen-induced T cell proliferation that effectively modulated immune system responses. Thus, these effect suggesting that WJ-MSC may be a good cellular resource for cell transplantation to treat MS [17].…”