Browsing by Author "Zangi, Lior"

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    Cardiac Sca-1+ cells are not intrinsic stem cells for myocardial development, renewal and repair
    (American Heart Association, 2018-12-18) Zhang, Lu; Sultana, Nishat; Yan, Jianyun; Yang, Fan; Chen, Fuxue; Chepurko, Elena; Yang, Feng-Chun; Du, Qinghua; Zangi, Lior; Xu, Mingjiang; Bu, Lei; Cai, Chen-Leng; Pediatrics, School of Medicine
    Background: For over a decade, Sca-1+ cells within the mouse heart have been widely recognized as a stem cell population with multipotency that can give rise to cardiomyocytes, endothelial cells and smooth muscle cells in vitro and after cardiac grafting. However, the developmental origin and authentic nature of these cells remain elusive. Methods: Here, we used a series of high-fidelity genetic mouse models to characterize the identity and regenerative potential of cardiac resident Sca-1+ cells. Results: With these novel genetic mouse models, we found that Sca-1 does not label cardiac precursor cells during early embryonic heart formation. Postnatal cardiac resident Sca-1+ cells are in fact a pure endothelial cell population. They retain endothelial properties and exhibit minimal cardiomyogenic potential during development, normal aging and upon ischemic injury. Conclusions: Our study provides definitive insights into the nature of cardiac resident Sca-1+ cells. The observations challenge the current dogma that cardiac resident Sca-1+ cells are intrinsic stem cells for myocardial development, renewal and repair and suggest that the mechanisms of transplanted Sca-1+ cells in heart repair need to be reassessed.
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    Pkm2 Regulates Cardiomyocyte Cell Cycle and Promotes Cardiac Regeneration
    (American Heart Association, 2020-04-14) Magadum, Ajit; Singh, Neha; Kurian, Ann Anu; Munir, Irsa; Mehmood, Talha; Brown, Kemar; Sharkar, Mohammad Tofael Kabir; Chepurko, Elena; Sassi, Yassine; Gyun, Jae; Lee, Philyoung; Santos, Celio X.C.; Gaziel-Sovran, Avital; Zhang, Guoan; Cai, Chen-Leng; Kho, Changwon; Mayr, Manuel; Shah, Ajay M.; Hajjar, Roger J.; Zangi, Lior; Pediatrics, School of Medicine
    Background: The adult mammalian heart has limited regenerative capacity, mostly attributable to postnatal cardiomyocyte cell cycle arrest. In the last 2 decades, numerous studies have explored cardiomyocyte cell cycle regulatory mechanisms to enhance myocardial regeneration after myocardial infarction. Pkm2 (Pyruvate kinase muscle isoenzyme 2) is an isoenzyme of the glycolytic enzyme pyruvate kinase. The role of Pkm2 in cardiomyocyte proliferation, heart development, and cardiac regeneration is unknown. Methods: We investigated the effect of Pkm2 in cardiomyocytes through models of loss (cardiomyocyte-specific Pkm2 deletion during cardiac development) or gain using cardiomyocyte-specific Pkm2 modified mRNA to evaluate Pkm2 function and regenerative affects after acute or chronic myocardial infarction in mice. Results: Here, we identify Pkm2 as an important regulator of the cardiomyocyte cell cycle. We show that Pkm2 is expressed in cardiomyocytes during development and immediately after birth but not during adulthood. Loss of function studies show that cardiomyocyte-specific Pkm2 deletion during cardiac development resulted in significantly reduced cardiomyocyte cell cycle, cardiomyocyte numbers, and myocardial size. In addition, using cardiomyocyte-specific Pkm2 modified RNA, our novel cardiomyocyte-targeted strategy, after acute or chronic myocardial infarction, resulted in increased cardiomyocyte cell division, enhanced cardiac function, and improved long-term survival. We mechanistically show that Pkm2 regulates the cardiomyocyte cell cycle and reduces oxidative stress damage through anabolic pathways and β-catenin. Conclusions: We demonstrate that Pkm2 is an important intrinsic regulator of the cardiomyocyte cell cycle and oxidative stress, and highlight its therapeutic potential using cardiomyocyte-specific Pkm2 modified RNA as a gene delivery platform.