Abstract
To explore how cardiac regeneration and cell turnover adapts to disease, different forms of stress were studied for their effects on the cardiac progenitor cell markers c-Kit and Isl1, the early cardiomyocyte marker Nkx2.5, and mast cells. Adult female rats were examined during pregnancy, after myocardial infarction and ischemia-reperfusion injury with/out insulin like growth factor-1(IGF-1) and hepatocyte growth factor (HGF). Different cardiac sub-domains were analyzed at one and two weeks post-intervention, both at the mRNA and protein levels. While pregnancy and myocardial infarction up-regulated Nkx2.5 and c-Kit (adjusted for mast cell activation), ischemia-reperfusion injury induced the strongest up-regulation which occurred globally throughout the entire heart and not just around the site of injury. This response seems to be partly mediated by increased endogenous production of IGF-1 and HGF. Contrary to c-Kit, Isl1 was not up-regulated by pregnancy or myocardial infarction while ischemia-reperfusion injury induced not a global but a focal up-regulation in the outflow tract and also in the peri-ischemic region, correlating with the up-regulation of endogenous IGF-1. The addition of IGF-1 and HGF did boost the endogenous expression of IGF and HGF correlating to focal up-regulation of Isl1. c-Kit expression was not further influenced by the exogenous growth factors. This indicates that there is a spatial mismatch between on one hand c-Kit and Nkx2.5 expression and on the other hand Isl1 expression. In conclusion, ischemia-reperfusion injury was the strongest stimulus with both global and focal cardiomyocyte progenitor cell marker up-regulations, correlating to the endogenous up-regulation of the growth factors IGF-1 and HGF. Also pregnancy induced a general up-regulation of c-Kit and early Nkx2.5+ cardiomyocytes throughout the heart. Utilization of these pathways could provide new strategies for the treatment of cardiac disease.
Highlights
The adult heart is not a terminally differentiated organ but maintains regenerative capacity through out life [1]
Despite of the recent enthusiasm, several issues remain unsolved, like which progenitor cells are responsible for the normal myocardial homeostasis and which stem cells are up-regulated most during a response to physiological and pathological stress? Many research groups have reported on different types of stem cell- like cells from different species
At the time of harvest, the hearts were divided into the different regions; outflow tract (OFT, defined as the outflow tract of the right ventricle), right ventricle (RV), left ventricle (LV), area of peri-infarct and peri-ischemia
Summary
The adult heart is not a terminally differentiated organ but maintains regenerative capacity through out life [1]. Many research groups have reported on different types of stem cell- like cells from different species These include cells with surface expression of molecules like stem cell antigen-1 (Sca-1) [4,5,6], Abcg2 [7,8,9], c-Kit [10,11,12,13,14,15] and the transcription factors Tbx 5 and Islet-1 (Isl1) [16,17,18,19]. Miyamoto and co-workers have isolated and successfully cultured c-Kit+ cells from adult rat hearts for 40 passages [13] These cells maintained their stem cell characteristics and could differentiate into cardiomyocytes, smooth muscle and endothelial cells. The isolated cardiomyocyte progenitor cells expressed moderate levels of c-Kit and could differentiate into cardiomyocytes after stimulation with 59azacytidine and TGF-b1.This finding further emphasizes the concept that c-Kit+ cells can be cardiomyocyte progenitor cells both in rodents and in man
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