Ischemia-reperfusion injury and pregnancy initiate time-dependent and robust signs of up-regulation of cardiac progenitor cells

• Published in: PloS one 2012-05, Vol.7 (5), p.e36804-e36804
• Main Authors: Genead, Rami, Fischer, Helene, Hussain, Alamdar, Jaksch, Marie, Andersson, Agneta B, Ljung, Karin, Bulatovic, Ivana, Franco-Cereceda, Anders, Elsheikh, Elzafir, Corbascio, Matthias, Smith, C I Edvard, Sylvén, Christer, Grinnemo, Karl-Henrik
• Format: Article
• Language: English
• Subjects: Anesthesiology; Angiogenesis; Animals; Antigens, Differentiation - biosynthesis; Apoptosis; Biology; c-Kit protein; Cardiology; Cardiomyocytes; Cell activation; Cells (biology); Coronary artery disease; Correlation; Female; Growth factors; Heart; Heart attack; Heart attacks; Heart diseases; Heart surgery; Hepatocyte growth factor; Hepatocyte Growth Factor - biosynthesis; Homeobox Protein Nkx-2.5; Homeodomain Proteins - biosynthesis; Injuries; Insulin; Insulin-like growth factor I; Insulin-Like Growth Factor I - biosynthesis; Insulin-like growth factors; Ischemia; Islet-1 protein; Laboratory animals; Mast cells; Mechanical properties; Medical treatment; Medicin och hälsovetenskap; Medicine; mRNA; Myocardial infarction; Myocardial Infarction - metabolism; Myocardial Infarction - pathology; Myocardial Reperfusion Injury - metabolism; Myocardial Reperfusion Injury - pathology; Myocytes, Cardiac - metabolism; Myocytes, Cardiac - pathology; Nkx2.5 protein; Physiology; Pregnancy; Pregnancy Complications, Cardiovascular - metabolism; Pregnancy Complications, Cardiovascular - pathology; Pregnant women; Progenitor cells; Proto-Oncogene Proteins c-kit - biosynthesis; Rats; Rats, Sprague-Dawley; Regeneration; Reperfusion; Reperfusion injury; RNA; Rodents; Smooth muscle; Stem cells; Stem Cells - metabolism; Stem Cells - pathology; Transcription factors; Transcription Factors - biosynthesis; Up-Regulation
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0036804

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.