Abstract
Significance The clinical utility of mesenchymal stromal/stem cells (MSCs) in mediating immunosuppressive effects and supporting regenerative processes is broadly established. However, the inherent heterogeneity of MSCs compromises its biomedical efficacy and reproducibility. To study how cellular variation affects fate decision-making processes, we perform single-cell RNA sequencing at multiple time points during bipotential matrix-directed differentiation toward soft- and stiff tissue lineages. In this manner, we identify distinctive MSC subpopulations that are characterized by their multipotent differentiation capacity and mechanosensitivity. Also, whole-genome screening highlights TPM1 as a potent mechanotransducer of matrix signals and regulator of cell differentiation. Thus, by introducing single-cell methodologies into mechanobiology, we delineate the complexity of adult stem cell responses to extracellular cues in tissue regeneration and immunomodulation.
Highlights
Mesenchymal stromal/stem cells (MSCs) form a heterogeneous population of multipotent progenitors that contribute to tissue regeneration and homeostasis
Brielle et al Delineating the heterogeneity of matrix-directed differentiation toward soft and stiff tissue lineages via single-cell profiling
To elucidate the transcriptional heterogeneity in response to tropomyosin knockdown and overexpression and the effects on Brielle et al Delineating the heterogeneity of matrix-directed differentiation toward soft and stiff tissue lineages via single-cell profiling cell fate decisions, we cultured TPM1.7, shTPM1, and Control MSCs for 3 d in basal medium and 3 d in bipotential medium and performed single-cell RNA profiling
Summary
Mesenchymal stromal/stem cells (MSCs) form a heterogeneous population of multipotent progenitors that contribute to tissue regeneration and homeostasis. To study how cellular variation affects fate decision-making processes, we perform single-cell RNA sequencing at multiple time points during bipotential matrixdirected differentiation toward soft- and stiff tissue lineages. In this manner, we identify distinctive MSC subpopulations that are characterized by their multipotent differentiation capacity and mechanosensitivity. To gain insight into the implications of MSC heterogeneity on cellular mechanosensitivity and multipotency, we transcriptionally profiled the cells via whole-genome single-cell RNA sequencing at nonconditioned, matrix-conditioned, and early differentiating stages. Characterizing cell-to-cell variations among the response to matrix and differentiation cues during cell state propagation contributes to elucidating MSC heterogeneity with future implications to cell-based therapeutics
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