MHC-class-II are expressed in a subpopulation of human neural stem cells in vitro in an IFNγ–independent fashion and during development

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.

Trends in tissue repair and regeneration

“…Using human neural stem cells, Patrizia Ferretti (University College London, UK) reported recent progress on the development of 3D culture systems to study neural damage. She also showed that in developing human brains major histocompatibility complex class II antigens (MHC-II) are unexpectedly expressed in the germinal zone in a subset of SOX2-positive neural progenitors (Vagaska et al, 2016). This expression, which is seemingly regulated independently of inflammatory stimuli, challenges the accepted notion that microglia are the only MHC-II-expressing cells in the developing CNS.…”

Modelling human CNS injury with human neural stem cells in 2- and 3-Dimensional cultures

“…Neuronal differentiation. A protocol previously modified from Sun et al 14,16 was used to induce neuronal differentiation of hNSCs 14,16 . After plating on Matrigel or laminin coated plates, hNSCs were maintained for 10 days in growth medium without EGF and then for further 7 days without EGF, FGF-2 and heparin to induce differentiation.…”

“…Whereas the use of iPSCs (induced pluripotent stem cells) derived from patients to study neural diseases has been rapidly expanding, there is still a lack of human injury models particularly in 3D 11-13 .Here we have used human neural stem cells (hNSCs) derived from embryonic and foetal brain as a cell source for setting up 3D cultures and injury models 10,14,15 . The advantage of hNSCs over iPSCs or hESCs (human embryonic stem cells) for this purpose is that they can proliferate extensively in vitro, have the potential to differentiate towards neurons, astrocytes and oligodendrocytes and are less demanding than iPSCs to maintain in culture [14][15][16][17][18] . Furthermore, in comparison with iPSCs, hNSCs differentiation protocols are in general much shorter, as they do not require the initial phase of inducing the cells towards neural progenitors.We set out to establish and evaluate a 3D human cell culture system using hydrogel scaffolds in order to mimic in vivo CNS tissue architecture while maintaining reproducibility and minimising variation found in open Scientific RepoRtS | (2020) 10:6785 | https://doi.org/10.1038/s41598-020-62906-y www.nature.com/scientificreports www.nature.com/scientificreports/ Figure 1.…”

“…Here we have used human neural stem cells (hNSCs) derived from embryonic and foetal brain as a cell source for setting up 3D cultures and injury models 10,14,15 . The advantage of hNSCs over iPSCs or hESCs (human embryonic stem cells) for this purpose is that they can proliferate extensively in vitro, have the potential to differentiate towards neurons, astrocytes and oligodendrocytes and are less demanding than iPSCs to maintain in culture [14][15][16][17][18] . Furthermore, in comparison with iPSCs, hNSCs differentiation protocols are in general much shorter, as they do not require the initial phase of inducing the cells towards neural progenitors.…”

Transplantation in the nonhuman primate MPTP model of Parkinson's disease: update and perspectives

“…Fetal VM tissue expresses MHC antigens that can elicit an immune response in the case of host mismatch (Widner et al, 1989). Expression level of MHC molecules is low in human PSCs and NSCs (Drukker et al, 2002;Vagaska et al, 2016) but can rapidly be induced in inflammatory conditions or following differentiation in vitro (Drukker and Benvenisty, 2004;Vagaska et al, 2016).…”