The Oxygen-Rich Postnatal Environment Induces Cardiomyocyte Cell-Cycle Arrest Through DNA Damage Response . Puente et al Cell . 2014;157:565–579 Mammalian hearts transition from a hypoxic in utero environment to an oxygen-rich habitat after birth, coinciding with the rapid postnatal exit of cardiomyocytes out of the cell cycle. A recent article in Cell identified a novel connection between the 2 seminal events, focusing on the accumulation of reactive oxygen species in cardiomyocytes as a major mediator of the critical neonatal cell cycle switch. Among the 11 major organ systems of the human body, only a selected few are capable of regenerating after organ damage, with considerable disparity in efficiency between amphibians, fishes, and mammals. The skin, bone marrow, intestine, and liver regenerate relatively well, and a common gecko restores its tail more effectively than a fish can repair its tailfin.1,2 In humans, skeletal muscle has the ability to heal from injury. In contrast, cardiac muscle, which shares many common features, has limited capacity to regenerate after damage. What determinants account for these differences, and what can we learn from each organ or animal so we can attempt to recapitulate such factors in poorly reparative tissues? Currently, there are ≥2 potential avenues by which the limited amount of cellular replenishment may occur in the mammalian heart. The first involves the proliferation and differentiation of resident cardiac progenitor cells bearing markers, such as cKit, Sca1, and Isl1. Self-renewing progenitor cells expressing some or all of these markers exist in defined microenvironments in vivo and possess properties of clonal expansion and multipotency ex vivo. Incongruent reports have suggested that, although clonal Lin-cKit+ cells isolated from adult mouse hearts can repopulate the myocardium after cardiac injury (myocardial infarction),3,4 the frequency at which this phenomena …