Browsing by Subject "Cardiac regeneration"

Now showing 1 - 6 of 6
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    Hand2 elevates cardiomyocyte production during zebrafish heart development and regeneration
    (The Company of Biologists, 2014-08) Schindler, Yocheved L.; Garske, Kristina M.; Wang, Jinhu; Firulli, Beth A.; Firulli, Anthony B.; Poss, Kenneth D.; Yelon, Deborah; Department of Pediatrics, IU School of Medicine
    Embryonic heart formation requires the production of an appropriate number of cardiomyocytes; likewise, cardiac regeneration following injury relies upon the recovery of lost cardiomyocytes. The basic helix-loop-helix (bHLH) transcription factor Hand2 has been implicated in promoting cardiomyocyte formation. It is unclear, however, whether Hand2 plays an instructive or permissive role during this process. Here, we find that overexpression of hand2 in the early zebrafish embryo is able to enhance cardiomyocyte production, resulting in an enlarged heart with a striking increase in the size of the outflow tract. Our evidence indicates that these increases are dependent on the interactions of Hand2 in multimeric complexes and are independent of direct DNA binding by Hand2. Proliferation assays reveal that hand2 can impact cardiomyocyte production by promoting division of late-differentiating cardiac progenitors within the second heart field. Additionally, our data suggest that hand2 can influence cardiomyocyte production by altering the patterning of the anterior lateral plate mesoderm, potentially favoring formation of the first heart field at the expense of hematopoietic and vascular lineages. The potency of hand2 during embryonic cardiogenesis suggested that hand2 could also impact cardiac regeneration in adult zebrafish; indeed, we find that overexpression of hand2 can augment the regenerative proliferation of cardiomyocytes in response to injury. Together, our studies demonstrate that hand2 can drive cardiomyocyte production in multiple contexts and through multiple mechanisms. These results contribute to our understanding of the potential origins of congenital heart disease and inform future strategies in regenerative medicine.
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    The heart of the neural crest: cardiac neural crest cells in development and regeneration
    (The Company of Biologists, 2020-10-15) George, Rajani M.; Maldonado-Velez, Gabriel; Firulli, Anthony B.; Pediatrics, School of Medicine
    Cardiac neural crest cells (cNCCs) are a migratory cell population that stem from the cranial portion of the neural tube. They undergo epithelial-to-mesenchymal transition and migrate through the developing embryo to give rise to portions of the outflow tract, the valves and the arteries of the heart. Recent lineage-tracing experiments in chick and zebrafish embryos have shown that cNCCs can also give rise to mature cardiomyocytes. These cNCC-derived cardiomyocytes appear to be required for the successful repair and regeneration of injured zebrafish hearts. In addition, recent work examining the response to cardiac injury in the mammalian heart has suggested that cNCC-derived cardiomyocytes are involved in the repair/regeneration mechanism. However, the molecular signature of the adult cardiomyocytes involved in this repair is unclear. In this Review, we examine the origin, migration and fates of cNCCs. We also review the contribution of cNCCs to mature cardiomyocytes in fish, chick and mice, as well as their role in the regeneration of the adult heart.
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    Mesenchymal Stem Cell-Derived Exosomal microRNAs in Cardiac Regeneration
    (MDPI, 2023-12-11) Bhaskara, Meghana; Anjorin, Olufisayo; Wang, Meijing; Surgery, School of Medicine
    Mesenchymal stem cell (MSC)-based therapy is one of the most promising modalities for cardiac repair. Accumulated evidence suggests that the therapeutic value of MSCs is mainly attributable to exosomes. MSC-derived exosomes (MSC-Exos) replicate the beneficial effects of MSCs by regulating various cellular responses and signaling pathways implicated in cardiac regeneration and repair. miRNAs constitute an important fraction of exosome content and are key contributors to the biological function of MSC-Exo. MSC-Exo carrying specific miRNAs provides anti-apoptotic, anti-inflammatory, anti-fibrotic, and angiogenic effects within the infarcted heart. Studying exosomal miRNAs will provide an important insight into the molecular mechanisms of MSC-Exo in cardiac regeneration and repair. This significant information can help optimize cell-free treatment and overcome the challenges associated with MSC-Exo therapeutic application. In this review, we summarize the characteristics and the potential mechanisms of MSC-derived exosomal miRNAs in cardiac repair and regeneration.
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    Musings on intrinsic cardiomyocyte cell cycle activity and myocardial regeneration
    (Elsevier, 2023) Soonpaa, Mark H.; Reuter, Sean P.; Castelluccio, Peter F.; Field, Loren J.; Pediatrics, School of Medicine
    Although the myocardial renewal rate in the adult mammalian heart is quite low, recent studies have identified genetic variants which can impact the degree of cardiomyocyte cell cycle reentry. Here we use the compound interest law to model the level of regenerative growth over time in mice exhibiting different rates of cardiomyocyte cell cycle reentry following myocardial injury. The modeling suggests that the limited ability of S-phase adult cardiomyocytes to progress through cytokinesis, rather than the ability to reenter the cell cycle per se, is a major contributor to the low levels of intrinsic regenerative growth in the adult myocardium.
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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.
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    Retraction Note: REST regulates the cell cycle for cardiac development and regeneration
    (Springer Nature, 2024-02-22) Zhang, Donghong; Wang, Yidong; Lu, Pengfei; Wang, Ping; Yuan, Xinchun; Yan, Jianyun; Cai, Chenleng; Chang, Ching-Pin; Zheng, Deyou; Wu, Bingruo; Zhou, Bin; Medicine, School of Medicine
    Retraction to: Nature Communications 10.1038/s41467-017-02210-y, published online 07 December 2017 The authors have retracted this article because of significant concerns regarding a number of figures presented in this work that question the integrity of the data. After publication, several concerns were raised about the figures in this article. Specifically, * There appears to be a partial overlap between two panels of Figure 4e (bottom left corner for p21KO and top right for DKO). * There appears to be an overlap between a control panel from figure 2k and Rest imKO in Figure 5g (PH3 staining). * There appears to be image reuse between two samples in Figure 5g in the Aurora B staining row for Rest imKO and p21KO. * There appears to be an overlap between Figure 6f Ph3 staining for the Rest cDNA sample and Supplementary Fig. 6e, EdU staining, Rest cDNA, with fewer arrows and less visible DAPI staining. All authors agree with this retraction.