Regenerative repair is connected to early and specific structural, immune, and metabolic MSC signatures in adult mammals

Abstract

Abstract Adult mammals exhibit a limited capacity for tissue regeneration following injury and typically heal through scar formation. Mesenchymal stem/stroma cells (MSCs), which are phenotypically plastic and ubiquitous across tissues, play a critical role in maintaining tissue architecture during repair. We hypothesized that early events in regenerative and non-regenerative repair involve changes in MSC heterogeneity, which in turn determine repair outcomes. To test this hypothesis, we performed extensive single-cell RNA sequencing (scRNA-seq) in a mouse model of tissue injury. This model standardizes the comparison of non-regenerative and regenerative repair in adults with identical developmental stages and genetic backgrounds. Our analysis of MSCs during the early phases of tissue repair in adult mammals enabled the identification of distinct regenerative and non-regenerative MSC clusters, suggesting that specific MSC states may actively drive tissue repair outcomes. Furthermore, unsupervised approaches allowed us to revisit the functional signatures of MSCs centering on their impact on tissue structure (S), inflammation/immunity (I) and metabolism (M). By integrating these S, I and M functions, the SIM framework provides a conceptual model to interpret MSC behavior as a coordinated tissue-level response rather than a collection of isolated pleiotropic activities. This work positions MSCs at the center of the “SIM” triad, underscoring their pivotal role in tissue repair.