Cardiomyocyte proliferation and progenitor cell recruitment underlie therapeutic regeneration after myocardial infarction in the adult mouse heart.
Bottom Line: After MI, new cardiomyocytes arise from both progenitors as well as pre-existing cardiomyocytes.Transplantation of CDCs upregulates host cardiomyocyte cycling and recruitment of endogenous progenitors, while boosting heart function and increasing viable myocardium.The observed phenomena cannot be explained by cardiomyocyte polyploidization, bi/multinucleation, cell fusion or DNA repair.
Affiliation: Cedars-Sinai Heart Institute, Los Angeles, CA, USA.Show MeSH
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Mentions: We used an inducible fate mapping approach which provides efficient and highly specific cardiomyocyte labelling (Hsieh et al, 2007; Loffredo et al, 2011; Zhang et al, 2010). Bitransgenic mice were generated by crossbreeding female transgenic B6129-Tg(Myh6-cre/Esr1)1 Jmk/J (hereafter referred to as MerCreMer) mice with male B6.Cg-Tg(ACTB-Bgeo/GFP)21Lbe/J (hereafter referred to as ZEG) reporter mice. MerCreMer mice carry a fusion transgene of Cre recombinase flanked by Mer (mutated estrogen receptor ligand binding domains), driven by the cardiac α-myosin heavy chain promoter (encoded by Myh6); thus the Cre recombinase activity is tamoxifen-sensitive and cardiomyocyte-specific. ZEG reporter mice carry a lacZ transgene flanked by LoxP sites, followed by stop codons and then the GFP gene; therefore, upon excision of the LoxP sites and stop codons mediated by Cre recombinase activity, the reporter switches to GFP (driven by the β-actin promoter), permanently and specifically marking resident cardiomyocytes and their progeny as GFP+. No spontaneous expression of GFP was detected in non-tamoxifen-pulsed bitransgenic animals [confirming previous studies reporting very low rates of leakage in MerCreMer/ZEG mice (Hsieh et al, 2007)], while pulsed mice exhibited robust GFP expression (Fig 1B, Supporting Information Fig 1).
Affiliation: Cedars-Sinai Heart Institute, Los Angeles, CA, USA.