SDF1 gradient associates with the distribution of c-Kit+ cardiac cells in the heart

Outi Renko,Erja Mustonen,Anna-Maria Tolonen,Johanna Magga,Heikki Ruskoaho,Jaana Rysä,Raisa Serpi

doi:10.1038/s41598-018-19417-8

Abstract

Identification of the adult cardiac stem cells (CSCs) has offered new therapeutic possibilities for treating ischemic myocardium. CSCs positive for the cell surface antigen c-Kit are known as the primary source for cardiac regeneration. Accumulating evidence shows that chemokines play important roles in stem cell homing. Here we investigated molecular targets to be utilized in modulating the mobility of endogenous CSCs. In a four week follow-up after experimental acute myocardial infarction (AMI) with ligation of the left anterior descending (LAD) coronary artery of Sprague-Dawley rats c-Kit+ CSCs redistributed in the heart. The number of c-Kit+ CSCs in the atrial c-Kit niche was diminished, whereas increased amount was observed in the left ventricle and apex. This was associated with increased expression of stromal cell-derived factor 1 alpha (SDF1α), and a significant positive correlation was found between c-Kit+ CSCs and SDF1α expression in the heart. Moreover, the migratory capacity of isolated c-Kit+ CSCs was induced by SDF1 treatment in vitro. We conclude that upregulation of SDF1α after AMI associates with increased expression of endogenous c-Kit+ CSCs in the injury area, and show induced migration of c-Kit+ cells by SDF1.

Highlights

Heart failure (HF) is a major health problem affecting more than 23 million people globally[1] with a still increasing prevalence because of the aging of the population
Cardiomyocytes transfected with SDF1α significantly increase the SDF1α concentration in culture media, and subsequently attract more cardiac stem cells (CSCs) migration[33]
Hypoxia-inducible factor 1 (HIF-1) is a transcription factor that is expressed in response to a decrease in the partial pressure of cellular oxygen and activates genes involved in angiogenesis, glycolysis, and erythropoiesis[43,44]

Summary

Introduction

Heart failure (HF) is a major health problem affecting more than 23 million people globally[1] with a still increasing prevalence because of the aging of the population. CSCs positive for the cell surface antigen c-Kit have been reported as the primary source for cardiac regeneration after injury[7,12,13], their capacity to generate new cardiomyocytes is still not clear. A chemokine (C-X-C motif) receptor 4 (CXCR4)[26,27,28], and its ligand, stromal cell-derived factor 1 (SDF1) alpha, originally identified as a molecule secreted in bone marrow stromal cell lines attracting and stimulating the growth of B-cells[29,30,31], provide attraction to many different cell types during development and adult life[32], attracting for example lymphocytes and hematopoietic stem cells.

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