The phenotype and potential origin of nestin⁺cardiac myocyte-like cells following infarction

Abstract

Nestin+ cardiac myocyte-like cells were detected in the peri-infarct/infarct region of the ischemically damaged heart. The present study was undertaken to elucidate the phenotype and potential origin of nestin+ cardiac myocyte-like cells and identify stimuli implicated in their appearance. In the infarcted human and rat heart, nestin+ cardiac myocyte-like cells were morphologically and structurally immature, exhibited a desmin-immunoreactive striated phenotype, expressed the beta(1)-adrenergic receptor, and associated with an aberrant pattern of connexin-43 expression and/or organization. Nestin+ cardiac myocyte-like cells were detected 24 h postischemic injury and persisted in the infarcted rat heart for 9 mo. In the normal rat heart, cardiac progenitor transcriptional factors Nkx2.5/GATA4 were detected in a subpopulation of nestin+ neural stem cells. Following an ischemic insult, nestin+/Nkx2.5+ neural stem cells migrated to the peri-infarct/infarct region and appeared to be in a primordial state of differentiation to a nestin+ cardiac myocyte-like cell. The exposure of adult male rats to normobaric hypoxia (12% O2) for 10 days failed to promote the appearance of nestin+ cardiac myocyte-like cells. Following osmotic pump delivery of isoproterenol to normal adult rats, nestin+ cardiac myocyte-like cells were detected, albeit the response was modest and secondary to tissue loss. Thus ischemia-induced appearance of nestin+ cardiac myocyte-like cells apparently represents an adaptive response to heal the infarcted heart. Nkx2.5/GATA4 expression in a subpopulation of resident neural stem cells provides the appropriate phenotype for their potential differentiation to a nestin+ cardiac myocyte-like cell.

Nestin+cells and healing the infarcted heart

“…Following ischemic damage, nestin ϩ cells migrated to the infarct region, and work from our laboratory and others have reported their involvement in neural remodeling and de novo blood vessel formation as a cellular substrate of angiogenesis (6,20,21,26,50,53). Additional evidence supports the premise that a subpopulation of cardiac resident nestin ϩ cells may directly contribute to myocardial regeneration (5,26,53). Nestin expression was not limited to neural progenitor/stem cells since the intermediate filament protein was also detected in endothelial cells of newly formed blood vessels in the infarct region and a subpopulation of scarderived myofibroblasts (4,6,21).…”

“…The latter cells were partially elongated and appeared to be in a primordial state of differentiation possibly to a cardiac myocyte-like cell. These data and the findings by Tomita and colleagues (53) suggested that a subpopulation of rat cardiac resident nestin ϩ cells expressing GATA4/NKX2.5 may represent a novel cardiac progenitor stem cell pool implicated in myocardial regeneration during reparative fibrosis (5). The study by Tamura and colleagues (50) have in part substantiated the aforementioned premise as neural crest-derived stem cells [e.g., nestin ϩ , form spheres in the presence of EGF/bFGF, c-kit…”

“…Furthermore, the normal rat heart also contained a GATA4/NKX2.5 ϩ population lacking nestin expression and a nestin ϩ population lacking GATA4/NKX2.5 immunoreactivity (5). Following an ischemic insult to the rat heart, nestin/GATA4/NKX2.5 ϩ cells were detected at the peri-infarct/infarct region, and the transcriptional factors had translocated from the cytoplasm to the nucleus (5). A predominant number of GATA4/NKX2.5/nestin ϩ cells identified in the peri-infarct/infarct region were not associated with distinctive nestin-immunoreactive processes (5).…”

“…Following an ischemic insult to the rat heart, nestin/GATA4/NKX2.5 ϩ cells were detected at the peri-infarct/infarct region, and the transcriptional factors had translocated from the cytoplasm to the nucleus (5). A predominant number of GATA4/NKX2.5/nestin ϩ cells identified in the peri-infarct/infarct region were not associated with distinctive nestin-immunoreactive processes (5). The latter cells were partially elongated and appeared to be in a primordial state of differentiation possibly to a cardiac myocyte-like cell.…”

Nestin upregulation characterizes vascular remodeling secondary to hypertension in the rat

“…Despite the plethora of data supporting the premise that nestin expression identified a stem cell phenotype, recent studies have detected the intermediate filament protein in numerous non-stem cell populations during physiological growth and pathological remodeling. Nestin was highly expressed in developing skeletal myofibers and downregulated following maturation, upregulated in endothelial cells during reparative angiogenesis, and induced in mesangial cells following injury and in scar myofibroblasts and cardiac myocyte-like cells bordering the peri-infarct/infarct region of the ischemically damaged rodent and human heart (1,3,4,7,9,11,24,25,31,32). However, in contrast to neural progenitor/stem cells, expression of the intermediate filament protein in skeletal myofibers and endothelial cells was driven by the first intron of the nestin gene (1,42,43).…”