Abstract
Debate surrounds the question of whether the heart is a post-mitotic organ in part due to the lack of an in vivo model in which myocytes are able to actively regenerate. The current study describes the first such mouse model — a fetal myocardial environment grafted into the adult kidney capsule. Here it is used to test whether cells descended from bone marrow can regenerate cardiac myocytes. One week after receiving the fetal heart grafts, recipients were lethally irradiated and transplanted with marrow from green fluorescent protein (GFP)-expressing C57Bl/6J (B6) donors using normal B6 recipients and fetal donors. Levels of myocyte regeneration from GFP marrow within both fetal myocardium and adult hearts of recipients were evaluated histologically. Fetal myocardium transplants had rich neovascularization and beat regularly after 2 weeks, continuing at checkpoints of 1, 2, 4, 6, 8 and12 months after transplantation. At each time point, GFP-expressing rod-shaped myocytes were found in the fetal myocardium, but only a few were found in the adult hearts. The average count of repopulated myocardium with green rod-shaped myocytes was 996.8 cells per gram of fetal myocardial tissue, and 28.7 cells per adult heart tissue, representing a thirty-five fold increase in fetal myocardium compared to the adult heart at 12 months (when numbers of green rod-shaped myocytes were normalized to per gram of myocardial tissue). Thus, bone marrow cells can differentiate to myocytes in the fetal myocardial environment. The novel in vivo model of fetal myocardium in the kidney capsule appears to be valuable for testing repopulating abilities of potential cardiac progenitors.
Highlights
The common textbook beliefs have been that no new cardiac myocytes are generated after birth in mammals; that cardiac myocytes are terminally differentiated, beat continuously and rarely fatigue or die; and that the heart increases in size only through hypertrophy
Recent studies have challenged these beliefs, suggesting that cardiac myocytes are replaced throughout the lifespan [1,2,3,4,5], that myocytes can regenerate from resident cardiac progenitor cells (CPCs) [6] as well as from bone marrow [3,7,8,9,10,11,12], and that the human heart contains cycling myocytes undergoing mitosis and cytokinesis under normal and pathological conditions [1,2,13]
At week 1, a mass of blood vessels was localized near the fetal heart (Figure S1) that was a result of angiogenesis of sprouting from the preexisting vessels as they were green fluorescence protein (GFP) staining negative
Summary
The common textbook beliefs have been that no new cardiac myocytes are generated after birth in mammals; that cardiac myocytes are terminally differentiated, beat continuously and rarely fatigue or die; and that the heart increases in size only through hypertrophy. These beliefs were supported by the absence of mitotic figures in myocytes as well as the absence of new cardiac myocytes after cell loss caused by infarction. Significant numbers of GFP-expressing rod-shaped myocytes were observed in the fetal myocardium model from 2 weeks to 12 months after irradiation and GFP-labeled marrow transplantation
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