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: Immunocytochemistry of isolated cells revealed that cycling (BrdU+ or Ki67+ or H3P+) GFP+/αSA+ cardiomyocytes were smaller (Fig 4A–E) and more often mononucleated (Figs 4A–C and 9A–C), compared to non-cycling (BrdU−, or Ki67− or H3P−) GFP+/αSA+ cardiomyocytes, consistent with previous findings (Chen et al, 2007). Flow cytometric analysis confirmed that cycling endogenous cardiomyocytes (BrdU+/GFP+ cells) were smaller (decreased time of flight, decreased forward scatter area) and less granular/complex (decreased side scatter area) compared to non-cycling endogenous cardiomyocytes (BrdU−/GFP+; Supporting Information Fig 4). Tissue immunohistochemistry revealed that ∼90% of cycling resident cardiomyocytes after MI and CDC therapy were located in the peri-infarct area [Fig 5A–D and F; defined as the area within one low-power field from the edges of the scar, but not including the scar itself (Supporting Information Fig 5)]. Furthermore, BrdU+ cardiomyocytes appear to be structurally integrated with the surrounding myocardium, as they are connected by gap junctions to neighbouring non-cycling myocytes (Fig 5E). Within the border zone, vessel densities were comparable in areas adjacent to BrdU+ cardiomyocytes as compared to those remote from BrdU+ cardiomyocytes (Fig 5F). To unequivocally show that cycling myocytes are normally perfused, we performed ex vivo retrograde perfusion of hearts (obtained from BrdU-pulsed bitransgenic mice) with a fluorescent dye (Celltracker RED), followed by enzymatic dissociation. The vast majority (29 of 30) BrdU+ cardiomyocytes were positive for Celltracker RED; the percentage of Celltracker RED+ cardiomyocytes did not differ between BrdU+ and BrdU− GFP+ cardiomyocytes (Fig 5G). Given that access to infused Celltracker RED is haematogenous, we conclude that cycling myocytes are normally perfused.
Affiliation: Cedars-Sinai Heart Institute, Los Angeles, CA, USA.