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

Department of 1 Physiology, Montreal Heart Institute and Université de Montréal; ; Department of 2 Pharmacology, Montreal Heart Institute and Université de Montréal; and ; Department of 3 Medicine, Montreal Heart Institute and Université de Montréal; ; Department of 4 Research Center, Montreal Heart Institute and Université de Montréal; and ; 5 Department of Paediatrics, Montreal Children's Hospital, Montreal, Quebec, Canada Submitted 26 May 2009 ; accepted in final form 10 August 2009 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 β 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% O 2 ) 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. neural stem cells; ischemia; scar formation; β 1 -adrenergic receptor; connexin-43 Address for reprint requests and other correspondence: A. Calderone, 5000 Bélanger St. East, Montréal, Québec, H1T 1C8, Canada (e-mail: angelo.calderone{at}umontreal.ca ).