Mapping the Tissue‐of‐Origins of Mesenchymal Stromal Cells in Injury Repair

Abstract Culture‐expanded mesenchymal stromal cells (MSCs) are capable of fostering tissue regeneration after transplantation. However, the behavior and physiological role of endogenous MSCs in distal organ repair remain undetermined. In this study, a suite of genetic tools is generated to distinguish MSCs between tissues, and to map their fate in local, proximate, and distal organ repair. By single‐cell RNA‐sequencing, it is found that the transcriptomic profiles of most non‐bone marrow‐derived mesenchymal stromal cells (nonBM‐MSCs) exhibited high similarities, yet differed from that of bone marrow‐derived mesenchymal stromal cells (BM‐MSCs), especially in their less abundant secretome. Fate‐mapping experiments demonstrated that BM‐MSCs do not contribute to the formation of myofibroblasts during fibrosis or cancer‐associated fibroblasts (CAFs) during tumorigenesis. In contrast, MSCs from proximate tissues actively migrated to the site of bone fracture, where they contributed to the formation of fibrocartilaginous soft callus. During injury‐associated inflammation, local MSCs modulated the polarization of tissue‐resident macrophages, whereas BM‐MSCs mobilized monocytes to the site of inflammation. Conditional deletion of Ccl2 in BM‐MSCs, but not in colon‐resident MSCs, ameliorated colon inflammation and restored body weight after colitis. Thus, injury repair is orchestrated by MSCs from multiple sources, with local, proximate, and distal MSCs acting through different mechanisms.