Human Wharton’s Jelly-Derived Stem Cells Display Immunomodulatory Properties and Transiently Improve Rat Experimental Autoimmune Encephalomyelitis
Cognizant Comm. Corp.
Cell Transplantation, Vol. 24, pp. 2077–2098, 2015
0963-6897/15 $90.00 + .00 DOI: http://dx.doi.org/10.3727/096368914X685104
Raf Donders,* Marjan Vanheusden,* Jeroen F. J. Bogie,* Stylianos Ravanidis,* Kristof Thewissen,*Piet Stinissen,* Wilfried Gyselaers,*† Jerome J. A. Hendriks,* and Niels Hellings*
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.
WJ-MSCs show a promising expression profile for immunomodulatory and neurotrophic support. They actively interact with immune cells by suppressing the activation and proliferation of T cells, but also by modulating DC differentiation and maturation. Upon transplantation WJ-MSCs transiently improve the clinical symptoms of severe chronic EAE, through temporary modulation of the host immune responses in the periphery. Though most of the allograft is cleared after injection, a small number of cells survived up to 3 weeks. Here they appeared to interact with alveolar and splenic macrophages, suggestive of ongoing immune modulation. Despite the fact that WJ-MSCs display a promising phenotype for future intervention strategies in MS, our in vivo data warrant further investigation into the immunological and regenerative potential of the cells. The fact that recovery was not permanent may raise the question if these stem cells are truly exerting regenerative effects. Furthermore, any regenerative effect would be useless if the damaging inflammatory environment still persists over time. As such, more elaborate research is needed concerning the molecular pathways underlying the protective mechanisms for induction of immune tolerance and tissue regeneration. Future research should address the different interactions of WJ cells with the alveolar and splenic immune compartment, investigating the in vivo modulation of macrophages and other immune cells. The immunological communication between WJ-MSCs and resident immune cells is likely to be different from that observed in vitro. Cell–cell communications in vivo might change the immunological status of the stem cells and consequently alter their therapeutic potential. We suggest that this is a multistep process involving cellular interactions with subsequent immunological activation and paracrine secretion of trophic factors. In such a scenario, the transplantation behavior of WJ-MSCs should be further detailed, addressing ways to sustain survival, reduce immune rejection, and increase homing toward damaged CNS tissue. Tracking WJ-MSCs using magnetic resonance or bioluminescence imaging should provide clues regarding their survival and distribution after application. Finally, as immunomodulation alone is not sufficient to combat disease pathology and the neuroprotective activity of WJ-MSCs needs to be further investigated, it is too early to conclude that WJ-MSCs can replace or complement existing MS drugs. To evaluate whether stem cells have an added therapeutic value, a thorough characterization of their neurotrophic mechanisms in vivo is essential. By transplanting WJ-MSCs in well-characterized de- and remyelination models, such as the lysolecithin or ethidium bromide demyelination model (8,83), the regenerative potential of WJ-MSCs can be further defined.