Cardiac disease or injury frequently leads to heart failure because the mammal heart cannot regenerate damaged myocardial tissue. The non-regeneration is primarily driven by the inability to proliferate in cardiomyocytes. On the other hand, cardiomyocytes are robustly proliferative during the final weeks of fetal development. Cardiomyocytes may continue proliferating up to seven days after birth. So, when myocardial infarction (MI) is induced on postnatal day (P) 1 in newborn mice, the animals recovered completely by P28 with no decline in cardiac function and negligible myocardial scarring. Furthermore, this recovery ability is virtually dismissed if MI is induced on P7 and later time points.

 

       Our lab is among the first team who experimented with and verified heart regeneration in pigs, a large-animal model very similar to the human heart. The gradually-declined regenerative capability was strongly associated with the lower rate of pig cardiomyocyte proliferation. We found that after birth, pig cardiomyocytes still exercised the cell cycle, which explained why they proliferate. However, they stopped cell cycling a few days after birth, therefore, unable to proliferate, and the heart failed to regenerate.

 

       Furthermore, we found that if the neonatal pigs undergo a cardiac injury on P1, they will not only completely recover on P28 but also recover after a second MI injury induced on P28. Thus, we were the first lab to extend the mammal heart regeneration windows from seven to at least twenty-eight days after birth. Analyzing the genetic data in these pigs’ cardiomyocytes, we discovered that important cell cycle regulators were significantly elevated after the neonatal P1 injury. Then, when they recover on P28, although cardiomyocytes did not need cell cycling, a number of these regulators, particularly TBX5, TBX20, and ERBB4, maintain high expression. Also, these regulators are required in heart development during the fetal and early-postnatal periods.

 

       Collectively, these provocative observations suggest that it may be possible to reactivate the cell cycle in cardiomyocytes of adult mammalian hearts, which could lead to the development of transformative new therapies for the treatment of myocardial disease.

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Read more: 

- Zhu W, Zhang E, Zhao M, Chong Z, Fan C, Tang Y, Hunter JD, Borovjagin AV, Walcott GP, Chen JY, Qin G, Zhang J. Regenerative Potential of Neonatal Porcine Hearts. Circulation. 2018 Dec 11;138(24):2809-2816. Epub 2018 July 20. PMID: 30030418; PMCID: PMC6301098

- Zhao M, Zhang E, Wei Y, Zhou Y, Walcott GP, Zhang J. Apical Resection Prolongs the Cell Cycle Activity and Promotes Myocardial Regeneration after LV Injury in Neonatal Pig.  Circulation 2020;142:913–916

- Nguyen, T.M., Wei, Y., Nakada, Y., Zhou, Y. and Zhang, J., Cardiomyocyte cell-cycle regulation in neonatal large mammals: Single Nucleus RNA-sequencing Data analysis via an Artificial-intelligence–based pipeline. Frontiers in Bioengineering and Biotechnology, p.972.

- Nakada, Y., Zhou, Y., Gong, W., Zhang, E.Y., Skie, E., Nguyen, T., Wei, Y., Zhao, M., Chen, W., Sun, J. and Raza, S.N., 2022. Single Nucleus Transcriptomics: Apical Resection in Newborn Pigs Extends the Time Window of Cardiomyocyte Proliferation and Myocardial Regeneration. Circulation, 145(23), pp.1744-1747.

- Steinhauser ML and Lee RT. Regeneration of the heart. EMBO Mol Med. 2011;3:701-12.