BioAcyl Corp
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Zhu, Y. (2024). Asparagine Synthetase Marks a Distinct Dependency Threshold for Cardiomyocyte Dedifferentiation. Circulation, 149(23). Added by: Dr. Enrique Feoli (07/09/2026, 15:21) Last edited by: Dr. Enrique Feoli (07/09/2026, 15:42) |
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| Resource type: Journal Article Published BibTeX citation key: Zhu2024 View all bibliographic details  |
Categories: BioAcyl Corp Subcategories: Cell reprogramming Creators: Zhu Collection: Circulation |
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| Abstract |
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BACKGROUND: Adult mammalian cardiomyocytes have limited proliferative capacity, but in specifically induced contexts they traverse through cell-cycle reentry, offering the potential for heart regeneration. Endogenous cardiomyocyte proliferation is preceded by cardiomyocyte dedifferentiation (CMDD), wherein adult cardiomyocytes revert to a less matured state that is distinct from the classical myocardial fetal stress gene response associated with heart failure. However, very little is known about CMDD as a defined cardiomyocyte cell state in transition. METHODS: Here, we leveraged 2 models of in vitro cultured adult mouse cardiomyocytes and in vivo adeno-associated virus serotype 9 cardiomyocyte–targeted delivery of reprogramming factors (Oct4, Sox2, Klf4, and Myc) in adult mice to study CMDD. We profiled their transcriptomes using RNA sequencing, in combination with multiple published data sets, with the aim of identifying a common denominator for tracking CMDD. RESULTS: RNA sequencing and integrated analysis identified Asparagine Synthetase (Asns) as a unique molecular marker gene well correlated with CMDD, required for increased asparagine and also for distinct fluxes in other amino acids. Although Asns overexpression in Oct4, Sox2, Klf4, and Myc cardiomyocytes augmented hallmarks of CMDD, Asns deficiency led to defective regeneration in the neonatal mouse myocardial infarction model, increased cell death of cultured adult cardiomyocytes, and reduced cell cycle in Oct4, Sox2, Klf4, and Myc cardiomyocytes, at least in part through disrupting the mammalian target of rapamycin complex 1 pathway. CONCLUSIONS: We discovered a novel gene Asns as both a molecular marker and an essential mediator, marking a distinct threshold that appears in common for at least 4 models of CMDD, and revealing an Asns/mammalian target of rapamycin complex 1 axis dependency for dedifferentiating cardiomyocytes. Further study will be needed to extrapolate and assess its relevance to other cell state transitions as well as in heart regeneration.
Added by: Dr. Enrique Feoli Last edited by: Dr. Enrique Feoli |
| Notes |
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Outcomes of in vivo reprogramming using OSKM. (A) In vivo full reprogramming leads to teratoma formation, a hallmark of pluripotency. Prematurely terminated OSKM expression results in dysplastic or cancerous growth, highlighting the tumorigenic risks associated with incomplete reprogramming. In contrast, in vivo partial OSKM reprogramming offers two distinct therapeutic benefits: (1) reduction of age-associated phenotypes, contributing to systemic rejuvenation, and (2) induction of regenerative phenotypes, which enhance tissue repair and regeneration without teratoma formation. This highlights the therapeutic potential of OSKM reprogramming while emphasizing the need to balance its benefits against the risks associated with full reprogramming. (B) Schematic of in vivo reprogramming through transient expression of OSK(M), which induces regeneration phenotypes in various organs and has broad potential for tissue repair and rejuvenation. The highlighted organs include the brain, heart, skeletal muscle, eyes, skin, liver, and intestines. Each box emphasizes the specific tissues in which regeneration has successfully been demonstrated, further supporting its potential for clinical applications in regenerative medicine and aging-related therapies. Added by: Dr. Enrique Feoli Last edited by: Dr. Enrique Feoli |
