title: 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.
authors.affiliation: Hasselt University, Biomedical Research Institute/Transnational University Limburg, School of Life Sciences, Diepenbeek, Belgium.
authors.forename: Raf
authors.initials: R
authors.lastname: Donders
authors.forename: Marjan
authors.initials: M
authors.lastname: Vanheusden
authors.forename: Jeroen F J
authors.initials: JF
authors.lastname: Bogie
authors.forename: Stylianos
authors.initials: S
authors.lastname: Ravanidis
authors.forename: Kristof
authors.initials: K
authors.lastname: Thewissen
authors.forename: Piet
authors.initials: P
authors.lastname: Stinissen
authors.forename: Wilfried
authors.initials: W
authors.lastname: Gyselaers
authors.forename: Jerome J A
authors.initials: JJ
authors.lastname: Hendriks
authors.forename: Niels
authors.initials: N
authors.lastname: Hellings
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000276:immunology / Q000502:physiology*; D049109:Cell Proliferation / Q000502:physiology; D016207:Cytokines / Q000378:metabolism; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000628:therapy*; D006801:Humans; D008213:Lymphocyte Activation / Q000276:immunology*; D059630:Mesenchymal Stem Cells / Q000166:cytology*; D051381:Rats; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology; D014470:Umbilical Cord / Q000166:cytology; D059631:Wharton Jelly / Q000166:cytology*
chemical_list: D016207:Cytokines