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Since the discovery of endothelial colony forming cells (ECFC), there has been significant interest in their therapeutic potential to treat vascular injuries. ECFC cultures display significant heterogeneity and a hierarchy among cells able to give rise to high proliferative versus low proliferative colonies. Here we aimed to define molecularly this in vitro hierarchy. Based on flow cytometry, CD34 expression levels distinguished two populations. Only CD34 + ECFC had the capacity to reproduce high proliferative potential (HPP) colonies on replating, whereas CD34− ECFCs formed only small clusters. CD34 + ECFCs were the only ones to self‐renew in stringent single‐cell cultures and gave rise to both CD34 + and CD34− cells. Upon replating, CD34 + ECFCs were always found at the centre of HPP colonies and were more likely in G0/1 phase of cell cycling. Functionally, CD34 + ECFC were superior at restoring perfusion and better engrafted when injected into ischemic hind limbs. Transcriptomic analysis identified cyclin‐dependent kinase (CDK) cell cycle inhibiting genes ( p16, p21 , and  p57 ), the Notch signaling pathway ( dll1, dll4, hes1 , and  hey1 ), and the endothelial cytokine  il33  as highly expressed in CD34 + ECFC. Blocking the Notch pathway using a γ‐secretase inhibitor (DAPT) led to reduced expression of cell cycle inhibitors, increased cell proliferation followed by a loss of self‐renewal, and HPP colony formation capacity reflecting progenitor exhaustion. Similarly shRNA knockdown of  p57  strongly affected self‐renewal of ECFC colonies. ECFC hierarchy is defined by Notch signalling driving cell cycle regulators, progenitor quiescence and self‐renewal potential. S tem  C ells   2016;34:902–912

stem cells

Self‐Renewal and High Proliferative Colony Forming Capacity of Late‐Outgrowth Endothelial Progenitors Is Regulated by Cyclin‐Dependent Kinase Inhibitors Driven by Notch Signaling