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.