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Circulation. 2018 Aug 21;138(8):793-805. doi: 10.1161/CIRCULATIONAHA.118.034250.

Genetic Lineage Tracing of Nonmyocyte Population by Dual Recombinases.

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The State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, and Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of Chinese Academy of Sciences, China (Yan Li, L.H., X.H., H.Z., S.Z., W.P., X.T., Yi Li, Q.L., W.Y., L.Z., X.L., K.L., J.T., H.Z., B.Z.).
Cardiovascular Division, British Heart Foundation Centre, King's College London, United Kingdom (S.I.B. Q.X.).
Key Laboratory of Regenerative Medicine of Ministry of Education, Jinan University, China (X.T., D.C., B.Z.).
Max Planck Institute for Molecular Biomedicine, Department of Tissue Morphogenesis, Faculty of Medicine, University of Muenster, Germany (A.H.R.).
Department of Chemical Pathology, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong SAR, China (K.O.L.).
School of Life Science and Technology, ShanghaiTech University, China (B.Z.).



Whether the adult mammalian heart harbors cardiac stem cells for regeneration of cardiomyocytes is an important yet contentious topic in the field of cardiovascular regeneration. The putative myocyte stem cell populations recognized without specific cell markers, such as the cardiosphere-derived cells, or with markers such as Sca1+, Bmi1+, Isl1+, or Abcg2+ cardiac stem cells have been reported. Moreover, it remains unclear whether putative cardiac stem cells with unknown or unidentified markers exist and give rise to de novo cardiomyocytes in the adult heart.


To address this question without relying on a particular stem cell marker, we developed a new genetic lineage tracing system to label all nonmyocyte populations that contain putative cardiac stem cells. Using dual lineage tracing system, we assessed whether nonmyocytes generated any new myocytes during embryonic development, during adult homeostasis, and after myocardial infarction. Skeletal muscle was also examined after injury for internal control of new myocyte generation from nonmyocytes.


By this stem cell marker-free and dual recombinases-mediated cell tracking approach, our fate mapping data show that new myocytes arise from nonmyocytes in the embryonic heart, but not in the adult heart during homeostasis or after myocardial infarction. As positive control, our lineage tracing system detected new myocytes derived from nonmyocytes in the skeletal muscle after injury.


This study provides in vivo genetic evidence for nonmyocyte to myocyte conversion in embryonic but not adult heart, arguing again the myogenic potential of putative stem cell populations for cardiac regeneration in the adult stage. This study also provides a new genetic strategy to identify endogenous stem cells, if any, in other organ systems for tissue repair and regeneration.


cell lineage; myocardial infarction; myocardial revascularization; myocytes, cardiac; recombinases; stem cell

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