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Human bone marrow-derived mesenchymal stromal/stem cells retain their trophic repair and immunoregulatory properties but lose their multipotent differentiation capacity after extensive ageing in vitro

ABSTRACT: To assess the hierarchical importance of multipotent differentiation compared with trophic/immunoregulatory functions of MSCs, we have undertaken a detailed analysis of how these properties change with in vitro ageing of the cells. Using in vitro differentiation and repair models and integrating transcriptomics and proteomics data, we show that the multipotent differentiation capacity of MSCs falls with increasing passage, whereas trophic repair and immunoregulatory potency are maintained.

ORGANISM(S): Homo sapiens

PROVIDER: GSE137186 | GEO | 2020/05/15

REPOSITORIES: GEO

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Project description:Mesenchymal stem cells (MSCs) are known to induce the conversion of activated T-cells into regulatory T-cells in vitro. The marker CD69 is a target of canonical NF-κB signaling and is transiently expressed upon activation; however, stable CD69 expression defines cells with immunoregulatory properties. Given its enormous therapeutic potential, we explored the molecular mechanisms underlying the induction of regulatory cells by MSCs. Peripheral blood CD3+ T-cells were activated and cultured in the presence or absence of MSCs. CD4+ cell mRNA expression was then characterized by microarray analysis. The drug BAY11-7082 and a siRNA against RELB were used to explore the differential roles of canonical and non-canonical NF-κB signaling, respectively. Flow cytometry and real-time PCR were used for analyses. Genes with immunoregulatory functions, CD69 and non-canonical NF-κB subunits (RELB and NFKB2) were all expressed at higher levels in lymphocytes co-cultured with MSCs. The frequency of CD69+ cells among lymphocytes cultured alone progressively decreased after activation. In contrast, the frequency of CD69+ cells increased significantly following activation in lymphocytes co-cultured with MSCs. Inhibition of canonical NF-κB signaling by BAY immediately following activation blocked the induction of CD69; however, inhibition of canonical NF-κB signaling on the 3rd day further induced the expression of CD69. Furthermore, late expression of CD69 was inhibited by RELB siRNA. These results indicate that the canonical NF-κB pathway controls the early expression of CD69 after activation; however, in an immunoregulatory context, late and sustained CD69 expression is promoted by the non-canonical pathway and is inhibited by canonical NF-κB signaling. In order to study the molecular basis by which Multipotent Mesenchymal Stromal/Stem Cells (MSC) exert their immune regulatory function, immunomagnetically purified CD3+ T-cells from the peripheral blood of 3 individuals were activated and cultured in the presence or absence of MSCs. Following 5 days, CD4+ and CD8+ T-cells were further immunomagnetically selected and their gene expression profiles were obtained by microarrays and compared. Paired samples from 3 individuals were used for this analysis.

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Human bone marrow-derived mesenchymal stromal/stem cells retain their trophic repair and immunoregulatory properties but lose their multipotent differentiation capacity after extensive ageing in vitro

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