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Transcriptional single cell analysis of human umbilical cord derived mesenchymal stem cells

ABSTRACT: Mesenchymal stem cells (MSCs) are a population of multipotent cells with an attractive ability to promote tissue repair by regulating regeneration and inflammation. Ironically, the immune regulatory capacity of MSCs, regardless of their tissue origin, is endowed by inflammatory cytokines (e.g., IFNg plus TNFa). Effective application of MSCs relies on the production of relatively homogeneous MSCs. However, the cellular heterogeneity, and the differentiation trajectories of in vitro expanded MSCs remains unclear. We profiled the transcriptomes of 361 single MSCs derived from two umbilical cords (UC-MSCs). The MSCs are from different passages and culture conditions with or without inflammatory cytokine stimulation. Weighted gene correlation network analysis for the expression of their highly variable genes revealed that UC-MSCs surprisingly possess only limited heterogeneity. Cell cycle based principal component analysis showed that the limited heterogeneity identified in these UC-MSCs was strongly associated with their entrance into the G2/M phase. This was further proven by the observation that one featured gene CD168 was expressed in a cell-cycle dependent manner. When CD168high UC-MSCs were sorted and cultured in vitro, they repopulated into a new community that is similar to the original status. Our results demonstrated that in vitro expanded UC-MSCs is a well-organized population with limited heterogeneity dominated by cell cycle status. Thus, our studies argues that standardization of MSCs for disease treatment is possible.

ORGANISM(S): Homo sapiens

PROVIDER: GSE117837 | GEO | 2019/05/15

REPOSITORIES: GEO

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Project description:Ex-vivo expanded mesenchymal stromal cells (MSCs) are increasingly used for paracrine support of hematopoietic stem cell (HSC) regeneration, but inconsistent outcomes have been the huddle for on-going clinical trials. Here, we hypothesized that the heterogeneity in the niche activity of manufactured MSCs can be a parameter for variable outcomes in MSC-based cell therapy. We first screened MSC culture medium and found that serum batches caused larger variations in colony forming unit-fibroblast (CFU-F) content of MSCs than individual donor variations. The culture conditions supporting high (stimulatory) and low (non-stimulatory) CFU-F caused distinct niche activity of MSCs; MSCs under stimulatory condition exhibited higher level expression of cross-talk molecules (Jagged-1 and CXCL-12) and higher support for HSCS during long-term culture than MSCs under non-stimulatory culture. Moreover, the effects of MSCs enhancing hematopoietic engraftment were only visible when HSCs were co-transplanted with MSCs expanded under stimulatory, but not non-stimulatory conditions. However, these differences of MSCs were readily reversed by switching the culture mediums, indicating their distinct functional state, rather than clonal heterogeneity. Accordingly, transcriptomic analysis showed distinct gene set enrichment between the different MSCs and revealed distinct upstream signaling pathways such as inhibition of P53 and activation of ATF4 for MSCs under stimulatory conditions. Taken together, our study shows that the heterogeneity in the niche activity of MSCs can be created during ex-vivo expansion to cause a difference in the hematopoietic engraftment and raise the possibility that MSCs can be pre-screened for more predictable outcomes in clinical trials of MSCs. Total RNA obtained from isolated human mesenchymal stromal cells. To compare stimulatory (SS) serum and non-stimulatory (NSS) serums, MSCs had been maintained in each serum media were sub-cultured for at least two passages before analysis.

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Transcriptional single cell analysis of human umbilical cord derived mesenchymal stem cells

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