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Single-Cell Transcriptome Atlas of Human Mesenchymal Stem Cells

ABSTRACT: The heterogeneity of mesenchymal stem cells (MSCs) remains incompletely inventoried, which often hampers reproducibility in clinical applications and basic research. Advanced single-cell RNA sequencing (scRNAseq) is a robust tool for dissecting cellular heterogeneity, while the comprehensive single-cell atlas still has not been achieved for human MSCs.Using massively parallel multiplexing scRNAseq, we constructed this atlas of >130,000 single-MSC transcriptomes across multiple tissues and donors to decipher their heterogeneity. The most widely clinical-utilized tissue-resources for MSCs were collected, including normal bone marrow (n=3), adipose (n=3), umbilical cord (n=2), and dermis (n=3).Based on this high-quality data, we identified the 7 tissue-specific and 5 conserved MSC subpopulations with distinct gene-expression signatures from multiple tissue origins, which has not been achieved previously. We noticed that extracellular matrix hugely contributes to MSC heterogeneity. Notably, tissue-specific MSC subpopulations exhibited hugely heterogeneous on ECM-associated immune regulation, antigen processing/presentation, and senescence, which also contributed to inter-donor and intra-tissue heterogeneity. The variable dynamics of ECM-associated genes depicted the discrete trajectory patterns across multiple tissues. Additionally, the conserved and tissue-specific transcriptomic-regulons and protein-protein interactions were identified, representing common or tissue-specific MSC potentially functional roles. Furthermore, we also discovered that the umbilical-cord-specific subpopulation possessed advantages in immunosuppressive properties.In summary, our work provides timely and exciting insights into MSC heterogeneity on multiple levels. In addition to resource value, this MSC atlas taxonomy provides a comprehensive understanding of cellular heterogeneity, revealing the potential improvements in MSC-based therapeutic efficacy.

ORGANISM(S): Homo sapiens

PROVIDER: GSE182158 | GEO | 2023/06/19

REPOSITORIES: GEO

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Project description:BACKGROUND: Perioperative neurocognitive disorder (PND) is a key complication affecting older individuals after anesthesia and surgery. Failure to translate multiple pharmacological therapies for PND from preclinical studies to clinical settings has necessitated the exploration of novel therapeutic strategies. Human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) treatment has emerged as a promising therapeutic strategy for treating neurodegenerative diseases and has the potential to translate basic science into clinical practice. In this study, we investigated the effects and underlying mechanism of hUC-MSCs on PND in aged mice.METHODS: hUC-MSCs were isolated from an infant umbilical cord and identified using flow cytometry and differentiation assays. We established PND model by undergoing aseptic laparotomy under isoflurane anesthesia maintaining spontaneous ventilation in 18-month-old male C57BL/6 mice. hUC-MSCs were slowly injected into mice by coccygeal vein before anesthesia. Cognitive function, neuroinflammation, neuroplasticity, endogenous neurogenesis and brain-derived neurotrophic factor (BDNF) were assessed. To determine the mechanisms underlying by which hUC-MSCs mediate their neuroprotective effects in PND, K252a, an antagonist of BDNF receptor, was administered intraperitoneally before surgery. Hippocampal BDNF/TrkB/CREB signaling pathway and metabolomic signatures were evaluated.RESULTS: hUC-MSC treatment ameliorated the learning and memory impairment in aged mice with PND. The downstream effects were the suppression of neuroinflammatory responses and restoration of neurogenesis and neuroplasticity dysregulation. Interestingly, the level of mature BDNF, but not that of proBDNF, was increased in the hippocampus after hUC-MSC treatment. Further analysis revealed that the improved cognitive recovery and the restoration of neurogenesis and neuroplasticity dysregulation elicited by exposure to hUC-MSCs were, at least partially, mediated by the activation of the BDNF/TrkB/CREB signaling pathway. Untargeted metabolomic further identified lipid metabolism dysfunction as potential downstream of the BDNF/TrkB/CREB signaling pathway in hUC-MSC-mediated neuroprotection for PND.CONCLUSIONS: Our study highlights the beneficial effects of hUC-MSC treatment on PND and provides a justification to consider the potential use of hUC-MSCs in the perioperative period.

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Single-Cell Transcriptome Atlas of Human Mesenchymal Stem Cells

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