title: 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.
authors.affiliation: Division of Cardiology, Department of Medicine, Karolinska Institutet, Stockholm, Sweden. rami.genead@ki.se
authors.forename: Rami
authors.initials: R
authors.lastname: Genead
authors.forename: Helene
authors.initials: H
authors.lastname: Fischer
authors.forename: Alamdar
authors.initials: A
authors.lastname: Hussain
authors.forename: Marie
authors.initials: M
authors.lastname: Jaksch
authors.forename: Agneta B
authors.initials: AB
authors.lastname: Andersson
authors.forename: Karin
authors.initials: K
authors.lastname: Ljung
authors.forename: Ivana
authors.initials: I
authors.lastname: Bulatovic
authors.forename: Anders
authors.initials: A
authors.lastname: Franco-Cereceda
authors.forename: Elzafir
authors.initials: E
authors.lastname: Elsheikh
authors.forename: Matthias
authors.initials: M
authors.lastname: Corbascio
authors.forename: C I Edvard
authors.initials: CI
authors.lastname: Smith
authors.forename: Christer
authors.initials: C
authors.lastname: Sylvén
authors.forename: Karl-Henrik
authors.initials: KH
authors.lastname: Grinnemo
mesh_terms: D000818:Animals; D000943:Antigens, Differentiation / Q000096:biosynthesis*; D005260:Female; D017228:Hepatocyte Growth Factor / Q000096:biosynthesis; D000072576:Homeobox Protein Nkx-2.5; D018398:Homeodomain Proteins / Q000096:biosynthesis; D007334:Insulin-Like Growth Factor I / Q000096:biosynthesis; D009203:Myocardial Infarction / Q000378:metabolism* / Q000473:pathology; D015428:Myocardial Reperfusion Injury / Q000378:metabolism* / Q000473:pathology; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology; D011247:Pregnancy; D011249:Pregnancy Complications, Cardiovascular / Q000378:metabolism* / Q000473:pathology; D019009:Proto-Oncogene Proteins c-kit / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D013234:Stem Cells / Q000378:metabolism* / Q000473:pathology; D014157:Transcription Factors / Q000096:biosynthesis; D015854:Up-Regulation
chemical_list: D000943:Antigens, Differentiation; D000072576:Homeobox Protein Nkx-2.5; D018398:Homeodomain Proteins; C524161:Nkx2-5 protein, rat; D014157:Transcription Factors; C548904:insulin-like growth factor-1, rat; D017228:Hepatocyte Growth Factor; D007334:Insulin-Like Growth Factor I; D019009:Proto-Oncogene Proteins c-kit