Ischemia-Reperfusion Injury and Pregnancy Initiate Time-Dependent and Robust Signs of Up-Regulation of Cardiac Progenitor Cells

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.

Human fetal cardiac progenitors: The role of stem cells and progenitors in the fetal and adult heart

“…These findings are supported by a report by Genead et al [61], where especially ischemiaereperfusion injury but also myocardial infarction induced a generalized upregulation of c-kit markers, which also correlated with the concomitant upregulation of the early cardiomyocyte marker Nkx2-5 [61]. Ischemiaereperfusion injury also caused a focal upregulation of Isl1 in the OFT and periischemic regions.…”

“…Even in the adult heart, a few resident Isl1-positive cells can be found in the OFT, expressing troponin T as a sign of cardiac commitment [61]. Other proposed cardiac progenitors in the adult heart are c-kitþ cells, Sca-1þ cells, platelet-derived growth factor receptor (PDGFR)-aþcells, SSEA-1þ cells, and side population cells [4,5,62e67].…”

Developmental origin and lineage plasticity of endogenous cardiac stem cells

“…Not only are they very rare, but there is evidence against their involvement in the regenerative post-injury response. No ISL1 + cells were found in the infarct region after myocardial infarction (Weinberger et al, 2012) and only focal expansion of cells was seen after ischemia-reperfusion injury (Genead et al, 2012). However, human and mouse ESCs bearing Isl1 reporters have been used to enrich for ISL1 + progenitors, which were able to differentiate into cardiomyocytes, endothelial cells and smooth muscle cells in vitro (Bu et al, 2009;Moretti et al, 2006;Qyang et al, 2007).…”

Fertilität und Lebensdauer

“…Im Tierversuch konnten bei schwangeren Mäusen und Ratten ein protektiver Effekt in Bezug auf ischämische Herzerkrankungen sowie eine Hochregulierung von kardialen Stammzellen beobachtet werden, weshalb weitere Studien mit plazentaren Derivaten für einen therapeutischen Ansatz angestrebt werden [8,21].…”