Abstract
Expression of major histocompatibility antigens class-2 (MHC-II) under non-inflammatory conditions is not usually associated with the nervous system. Comparative analysis of immunogenicity of human embryonic/fetal brain-derived neural stem cells (hNSCs) and human mesenchymal stem cells with neurogenic potential from umbilical cord (UC-MSCs) and paediatric adipose tissue (ADSCs), while highlighting differences in their immunogenicity, led us to discover subsets of neural cells co-expressing the neural marker SOX2 and MHC-II antigen in vivo during human CNS development. MHC-II proteins in hNSCs are functional, and differently regulated upon differentiation along different lineages. Mimicking an inflammatory response using the inflammatory cytokine IFNγ induced MHC-II up-regulation in both astrocytes and hNSCs, but not in UC-MSCs and ADSCs, either undifferentiated or differentiated, though IFNγ receptor expression was comparable. Together, hypoimmunogenicity of both UC-MSCs and ADSCs supports their suitability for allogeneic therapy, while significant immunogenicity of hNSCs and their progeny may at least in part underlie negative effects reported in some patients following embryonic neural cell grafts. Crucially, we show for the first time that MHC-II expression in developing human brains is not restricted to microglia as previously suggested, but is present in discrete subsets of neural progenitors and appears to be regulated independently of inflammatory stimuli.
Highlights
Studies[9,10]
We focused on mesenchymal cells that could be stably maintained and had the potential to be used for neural stem cell therapy, UC-mesenchymal stem cells (MSCs) and paediatric Adipose tissue-Derived Stem Cells (ADSCs)
Potential immunogenicity of Human Neural Stem Cells (hNSCs), Umbilical Cord Mesenchymal Stem Cells (UC-MSCs) and ADSCs was first investigated by comparing expression of the major histocompatibility complexes, HLA-A, -B, -C (MHC class I, MHC-I) and HLA-DR, -DP, -DQ (MHC class II, MHC-II), by flow cytometry analysis in 3 independent lines for each cell type
Summary
Studies[9,10]. results from in vivo animal studies show discrepancy in their conclusions, with immunoresponse to neural stem cells reported to be low by some, and significant by others[11,12,13]. The finding that no MHC-II protein expression was observed in UC-MSCs and ADSCs, whereas a significant subset of hNSCs were positive, raised the issues of 1) the identity of these cells, as within the normal central nervous system (CNS) MHC-II are believed to be expressed only by microglia, and 2) their existence in the developing human CNS. Our studies suggest the existence of a novel neural stem cell population within the developing human CNS constitutively expressing MHC-II, rather than as a consequence of an inflammatory reaction. These findings suggest that hNSCs and their progeny may mount an immune response when grafted for therapeutic purposes which may have serious implications for the outcome of the procedure and possibly account for negative outcome in some patients in clinical trials
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