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Single cell transcriptomic analysis of human mesenchymal stem cells reveals limited heterogeneity.

ABSTRACT: Mesenchymal stem cells (MSCs) are a population of multipotent cells with a superior ability to promote tissue repair by regulating regeneration and inflammation. Effective application of MSCs in disease treatment relies on the production of relatively homogeneous cell population. However, the cellular heterogeneity and the differentiation trajectories of in vitro expanded MSCs remain largely unclear. We profiled the transcriptomes of 361 single MSCs derived from two umbilical cords (UC-MSCs). These UC-MSCs were harvested at different passages and stimulated with or without inflammatory cytokines. Weighted gene correlation network analysis revealed that UC-MSCs surprisingly possess only limited heterogeneity, regardless of donors, and passages. We also found that upon pretreatment with inflammatory cytokines (IFN? and TNF?), a classical strategy that can improve the efficiency of MSC-based therapy, MSCs exhibited uniformed changes in gene expression. 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 again showed similar CD168 expression patterns. Our results demonstrated that in vitro expanded UC-MSCs are a well-organized population with limited heterogeneity dominated by cell cycle status. Thus, our studies provided information for standardization of MSCs for disease treatment.

SUBMITTER: Huang Y

PROVIDER: S-EPMC6506509 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

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Single cell transcriptomic analysis of human mesenchymal stem cells reveals limited heterogeneity.

Huang Yin Y Li Qing Q Zhang Kunshan K Hu Mingyuan M Wang Yu Y Du Liming L Lin Liangyu L Li Siguang S Sorokin Lydia L Melino Gerry G Shi Yufang Y Shi Yufang Y Wang Ying Y

Cell death & disease 20190508 5

Mesenchymal stem cells (MSCs) are a population of multipotent cells with a superior ability to promote tissue repair by regulating regeneration and inflammation. Effective application of MSCs in disease treatment relies on the production of relatively homogeneous cell population. However, the cellular heterogeneity and the differentiation trajectories of in vitro expanded MSCs remain largely unclear. We profiled the transcriptomes of 361 single MSCs derived from two umbilical cords (UC-MSCs). Th ...[more]

PMID: 31068579

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Project description:Despite the uniform selection criteria for the isolation of human mesenchymal stem cells (MSCs), considerable heterogeneity exists which reflects the distinct tissue origins and differences between individuals with respect to their genetic background and age. This heterogeneity is manifested by the variabilities seen in the transcriptomes, proteomes, secretomes, and epigenomes of tissue-specific MSCs. Here, we review literature on different aspects of MSC heterogeneity including the role of epigenetics and the impact of MSC heterogeneity on therapies. We then combine this with a meta-analysis of transcriptome data from distinct MSC subpopulations derived from bone marrow, adipose tissue, cruciate, tonsil, kidney, umbilical cord, fetus, and induced pluripotent stem cells derived MSCs (iMSCs). Beyond that, we investigate transcriptome differences between tissue-specific MSCs and pluripotent stem cells. Our meta-analysis of numerous MSC-related data sets revealed markers and associated biological processes characterizing the heterogeneity and the common features of MSCs from various tissues. We found that this heterogeneity is mainly related to the origin of the MSCs and infer that microenvironment and epigenetics are key drivers. The epigenomes of MSCs alter with age and this has a profound impact on their differentiation capabilities. Epigenetic modifications of MSCs are propagated during cell divisions and manifest in differentiated cells, thus contributing to diseased or healthy phenotypes of the respective tissue. An approach used to reduce heterogeneity caused by age- and tissue-related epigenetic and microenvironmental patterns is the iMSC concept: iMSCs are MSCs generated from induced pluripotent stem cells (iPSCs). During iMSC generation epigenetic and chromatin remodeling result in a gene expression pattern associated with rejuvenation thus allowing to overcome age-related shortcomings (e.g., limited differentiation and proliferation capacity). The importance of the iMSC concept is underlined by multiple clinical trials. In conclusion, we propose the use of rejuvenated iMSCs to bypass tissue- and age-related heterogeneity which are associated with native MSCs.

Project description:BackgroundMesenchymal stem/stromal cells (MSCs) are multipotent cells with a promising application potential in regenerative medicine and immunomodulation. However, MSCs cultured in vitro exhibit functional heterogeneity. The underlying molecular mechanisms that define MSC heterogeneity remain unclear.MethodsWe investigated the gene expression profile via single-cell RNA sequencing (scRNA-seq) of human primary Wharton's jelly-derived MSCs (WJMSCs) cultured in vitro from three donors. We also isolated CD142+ and CD142- WJMSCs based on scRNA-seq data and compared their proliferation capacity and "wound healing" potential in vitro. Meanwhile, we analyzed publicly available adipose-derived MSC (ADMSCs) scRNA-seq data and performed transcriptome comparison between WJMSCs and ADMSCs at the single-cell level.ResultsGO enrichment analysis of highly variable genes (HVGs) obtained from WJMSCs revealed that these genes are significantly enriched in extracellular region with binding function, involved in developmental process, signal transduction, cell proliferation, etc. Pathway analysis showed that these HVGs are associated with functional characteristics of classic MSCs, such as inflammation mediated by chemokine and cytokine signaling, integrin signaling, and angiogenesis. After regressing out the batch and cell cycle effects, these HVGs were used for dimension reduction and clustering analysis to identify candidate subpopulations. Differentially expressed gene analysis revealed the existence of several distinct subpopulations of MSCs that exhibit diverse functional characteristics related to proliferation, development, and inflammation response. In line with our data, sorted CD142+ and CD142- WJMSCs showed distinct proliferation capacity as well as "wound healing" potential. Although WJMSCs and ADMSCs were derived from different tissues and were displaying different differentiation potencies, their HVGs were largely overlapped and had similar functional enrichment.ConclusionHVGs identified in MSCs are associated with classic MSC function. Regarding therapeutic potential, these genes are associated with functional characteristics, on which the MSC clinical application were theoretically based, such as development and inflammation response. Altogether, these HVGs hold the potential to be used as candidate markers for further potency association studies.

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Single cell transcriptomic analysis of human mesenchymal stem cells reveals limited heterogeneity.

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Single cell transcriptomic analysis of human mesenchymal stem cells reveals limited heterogeneity.

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