A novel population of embryonic endothelial derived progenitors contributes to multiple mesodermal lineages during development and muscle regeneration

Several investigators have reported the isolation of vessel-associated multipotent mesodermal progenitors from diverse dissociated and cultured embryonic, fetal, perinatal and adult tissues. Despite the increasingly recognized medical value of these progenitor cells, among which are mesoangioblasts, these indirect extraction methods have precluded the understanding of their native identity, tissue distribution and frequency. We addressed this question by using a genetic lineage tracing approach. We labelled embryonic VE-Cadherin+ endothelial cells in the E8.5-E9 time window. At embryonic, foetal and perinatal stages, we detected labelled skeletal muscle, smooth muscle and dermis cells originating from embryonic endothelium as part of their in vivo normal developmental fate. We excluded that this contribution derives from a somitic intermediate progenitor. Consistently, we observed a small number of endothelial-derived muscle fibers in the adult skeletal muscle. We also found labelled subsets of pericytes and PICs (PW1+ interstitial progenitors), but we did not detect any labelled satellite cell. Following muscle damage, cells derived from embryonic endothelial progenitors participate to myogenic regenerative response, generating myofibers and macrophages. FACS-isolated endothelial derived cells are myogenic in vitro and are able to differentiate in several mesodermal tissues, including SMA (smooth muscle actin) positive cells, AP (alkaline phosphatase) positive osteoblast-like cells, adipose tissue and endothelial networks. Intra-muscular injection of isolated endothelial derived cells results in colonization and reconstitution of skeletal muscle tissue in both wild type and dystrophic mice. Moreover, we demonstrated that haematopoietic cells originated by endothelial to haematopoietic transition in the yolk sac emerge abluminally from vessels in the body of the embryo and migrate into the mesenchyme. We also identified a novel population of cells that express haematopoietic and mesenchymal markers and are originated by this process. These data suggest the existence of a previously unrecognized endothelial-derived progenitor cell population, which could represent the in vivo counterpart of embryonic mesoangioblasts. These progenitor cells contribute to smooth and skeletal muscle development, as part of their normal fate, and generate cells that persist in the adult life, participating to muscle regeneration.