Prolonged Myocardial Regenerative Capacity in Neonatal Opossum

Abstract

Background: Early neonates of both large and small mammals are able to regenerate the myocardium through cardiomyocyte proliferation for only a short period after birth. This myocardial regenerative capacity declines in parallel with withdrawal of cardiomyocytes from the cell cycle in the first few postnatal days. No mammalian species examined to date has been found capable of a meaningful regenerative response to myocardial injury later than 1 week after birth. Methods: We examined cardiomyocyte proliferation in neonates of the marsupial opossum ( Monodelphis domestica ) by immunostaining at various times after birth. The regenerative capacity of the postnatal opossum myocardium was assessed after either apex resection or induction of myocardial infarction at postnatal day 14 or 29, whereas that of the postnatal mouse myocardium was assessed after myocardial infarction at postnatal day 7. Bioinformatics data analysis, immunofluorescence staining, and pharmacological and genetic intervention were applied to determine the role of AMPK (5′-AMP–activated protein kinase) signaling in regulation of the mammalian cardiomyocyte cell cycle. Results: Opossum neonates were found to manifest cardiomyocyte proliferation for at least 2 weeks after birth at a frequency similar to that apparent in early neonatal mice. Moreover, the opossum heart at postnatal day 14 showed substantial regenerative capacity both after apex resection and after myocardial infarction injury, whereas this capacity had diminished by postnatal day 29. Transcriptomic and immunofluorescence analyses indicated that AMPK signaling is activated in postnatal cardiomyocytes of both opossum and mouse. Pharmacological or genetic inhibition of AMPK signaling was sufficient to extend the postnatal window of cardiomyocyte proliferation in both mouse and opossum neonates as well as of cardiac regeneration in neonatal mice. Conclusions: The marsupial opossum maintains cardiomyocyte proliferation and a capacity for myocardial regeneration for at least 2 weeks after birth. As far as we are aware, this is the longest postnatal duration of such a capacity among mammals examined to date. AMPK signaling was implicated as an evolutionarily conserved regulator of mammalian postnatal cardiomyocyte proliferation.

Cardiomyocyte maturation and its reversal during cardiac regeneration

“…In humans 86 and pigs, 84 10%–20% CMs are multinucleated at birth, which continues to increase afterwards. On the other hand, opossum CMs remain mononucleated for 2 weeks after birth, before a marked increase in ploidy from 1 month of age 94 . It will be interesting to investigate what contributes to the difference in the timing of polyploidization between these species.…”

Versican Promotes Cardiomyocyte Proliferation and Cardiac Repair

“…[39][40][41] In contrast, the neonatal mammalian heart possesses a unique ability to regenerate during the first week of life, and the regenerating cardiomyocytes are derived from preexisting cardiomyocytes. [5][6][7][42][43][44] Cardiomyocytes are embedded within a rich ECM network, which is a dynamic microenvironment that plays a vital role in heart regeneration and healing. [18][19][20][21][22][24][25][26] On the basis of the phenomenon of heart regeneration in neonatal mice, we focused on the role of ECM in this process to explore new factors for cardiac repair.…”

HRas and Myc synergistically induce cell cycle progression and apoptosis of murine cardiomyocytes

“…Here we observed Aurora B kinase localisation in cardiomyocytes in prophase, metaphase, anaphase/telophase and symmetrical mid-bodies. Mitotic kinesin-like protein 1 (Mklp1) is an additional marker of cardiomyocyte cytokinesis where it accumulates at the cleavage furrow ( 52 , 53 ). Here we observed Mklp1 staining at the cleavage furrow of cardiomyocytes in Myc/HRas overexpressing hearts.…”