Abstract
Cardiac regeneration involves the generation of new cardiomyocytes from cycling cardiomyocytes. Understanding cell-cycle activity of pre-existing cardiomyocytes provides valuable information to heart repair and regeneration. However, the anatomical locations and in situ dynamics of cycling cardiomyocytes remain unclear. Here we develop a genetic approach for a temporally seamless recording of cardiomyocyte-specific cell-cycle activity in vivo. We find that the majority of cycling cardiomyocytes are positioned in the subendocardial muscle of the left ventricle, especially in the papillary muscles. Clonal analysis revealed that a subset of cycling cardiomyocytes have undergone cell division. Myocardial infarction and cardiac pressure overload induce regional patterns of cycling cardiomyocytes. Mechanistically, cardiomyocyte cell cycle activity requires the Hippo pathway effector YAP. These genetic fate-mapping studies advance our basic understanding of cardiomyocyte cell cycle activity and generation in cardiac homeostasis, repair, and regeneration.
Highlights
Cardiac regeneration involves the generation of new cardiomyocytes from cycling cardiomyocytes
Considering that blood pressure is known to be higher in the left ventricle than the right ventricle[26], we examined whether altering chamber pressure can induce cardiomyocyte cell-cycle activity in the adult heart
Developing methods for tracing in vivo cardiomyocyte proliferation is fundamental for exploring the mechanisms of heart repair and regeneration, and provides new means of exploring therapeutic approach to promoting cardiomyocyte proliferation
Summary
Cardiac regeneration involves the generation of new cardiomyocytes from cycling cardiomyocytes. Cardiomyocyte cell cycle activity requires the Hippo pathway effector YAP These genetic fatemapping studies advance our basic understanding of cardiomyocyte cell cycle activity and generation in cardiac homeostasis, repair, and regeneration. Different from previously available methods which rely on the incorporation of nucleotide analogs[8,9], isotope analysis[4,5,10], or staining of proliferation markers by antibody[5,11], ProTracer is based on a tissue-specific and temporally seamless genetic fate mapping technology for monitoring of cell proliferation, enabling high resolution in the detection of the proliferation of one specific cell lineage. By applying ProTracer, we observed that the majority of cycling cardiomyocytes, as well as divided cardiomyocytes (~ 13% of traced cardiomyocytes) among them, are highly restricted to the subendocardial muscle of the left ventricle in adult hearts
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