Single‐cell transcriptome atlas of human mesenchymal stem cells exploring cellular heterogeneity

<jats:title>Abstract</jats:title><jats:sec><jats:title>Background</jats:title><jats:p>The heterogeneity of mesenchymal stem cells (MSCs) is poorly understood, thus limiting clinical application and basic research reproducibility. Advanced single‐cell RNA sequencing (scRNA‐seq) is a robust tool used to analyse for dissecting cellular heterogeneity. However, the comprehensive single‐cell atlas for human MSCs has not been achieved.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>This study used massive parallel multiplexing scRNA‐seq to construct an atlas of > 130 000 single‐MSC transcriptomes across multiple tissues and donors to assess their heterogeneity. The most widely clinically utilised tissue resources for MSCs were collected, including normal bone marrow (<jats:italic>n</jats:italic> = 3), adipose (<jats:italic>n</jats:italic> = 3), umbilical cord (<jats:italic>n</jats:italic> = 2), and dermis (<jats:italic>n</jats:italic> = 3).</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>Seven tissue‐specific and five conserved MSC subpopulations with distinct gene‐expression signatures were identified from multiple tissue origins based on the high‐quality data, which has not been achieved previously. This study showed that extracellular matrix (ECM) highly contributes to MSC heterogeneity. Notably, tissue‐specific MSC subpopulations were substantially heterogeneous on ECM‐associated immune regulation, antigen processing/presentation, and senescence, thus promoting inter‐donor and intra‐tissue heterogeneity. The variable dynamics of ECM‐associated genes had discrete trajectory patterns across multiple tissues. Additionally, the conserved and tissue‐specific transcriptomic‐regulons and protein‐protein interactions were identified, potentially representing common or tissue‐specific MSC functional roles. Furthermore, the umbilical‐cord‐specific subpopulation possessed advantages in immunosuppressive properties.</jats:p></jats:sec><jats:sec><jats:title>Conclusion</jats:title><jats:p>In summary, this work provides timely and great insights into MSC heterogeneity at multiple levels. This MSC atlas taxonomy also provides a comprehensive understanding of cellular heterogeneity, thus revealing the potential improvements in MSC‐based therapeutic efficacy.</jats:p></jats:sec>