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
Related in: MedlinePlus
Mentions: We next sought to determine the relative contributions of adult cardiomyocyte proliferation and cardiomyogenic differentiation of endogenous stem cells in postnatal cardiomyogenesis. 4-OH-Tamoxifen-pulsed 6–8 week-old bitransgenic mice were randomized to undergo: (a) sham surgery; (b) induction of MI by permanent LAD ligation; or (c) induction of MI followed by intramyocardial injection of mouse CDCs (2 × 105, grown from wild-type animals) into the infarct border zone. Mice were subsequently pulsed with daily BrdU injections for 5 weeks, at which point hearts were explanted and enzymatically dissociated. We used FACS-sorting (gating on large cells) to isolate GFP+ and GFP− cardiomyocytes (Fig 7A), which subsequently underwent flow cytometry for αSA expression and BrdU incorporation. Only αSA+ cells were examined (Fig 7A), in order to assure the purity of the GFP− fraction, and to avoid confounding results arising from contamination by GFP− non-myocytes. By comparing the rates of BrdU incorporation in GFP+ versus GFP− cardiomyocytes, we were able to calculate the absolute rates and relative magnitudes of induced secondary cardiomyocyte proliferation and cardiomyogenic differentiation of recruited endogenous stem cells in postnatal cardiomyogenesis in the normal, infarcted and CDC-treated hearts. Taking into account that GFP only marks preformed resident cardiomyocytes, equal rates of BrdU incorporation in GFP+ and GFP− myocytes would translate to no significant contribution of endogenous progenitors to the myocyte pool during the course of BrdU pulsing (as the cardiomyocytes arising from progenitors would by default be GFP−). Increased rates of BrdU incorporation in the GFP− myocyte fraction would translate to myogenic differentiation of progenitors during the course of BrdU pulsing.
Affiliation: Cedars-Sinai Heart Institute, Los Angeles, CA, USA.