Coculture with hematopoietic stem cells protects cardiomyocytes against apoptosis via paracrine activation of AKT

Journal of Translational Medicine

Research

Mark Rosenberg¹  Matthias Lutz¹  Constantin Kühl¹  Norbert Frey¹  Hugo A Katus²  Jutta Krebs²  Rainer Will²  Volker Eckstein³ 

[1] Department of Internal Medicine III (Cardiology and Angiology), University Medical Center Schleswig-Holstein, Campus Kiel, Schittenhelmstr.12, D-24105, Kiel, Germany;Department of Internal Medicine III, University of Heidelberg, Heidelberg, Germany;Department of Internal Medicine V, University of Heidelberg, Heidelberg, Germany;

关键词: Stem cells;    Cardiomyocytes;    Apoptosis;    Paracrine;   

DOI  :  10.1186/1479-5876-10-115

 received in 2011-09-22, accepted in 2012-06-06,  发布年份 2012

来源: Springer

【 摘 要 】

BackgroundPrevious experimental studies concluded that stem cells (SC) may exert their beneficial effects on the ischemic heart by paracrine activation of antiapoptotic pathways. In order to identify potential cardioprotective mediators, we performed a systematic analysis of the differential gene expression of hematopoietic SC after coculture with cardiomyocytes (CM).MethodsAfter 48 h of coculture with neonatal rat ventricular CM (NRVCM), two consecutive cell sorting steps generated a highly purified population of conditioned murine hematopoietic SC (>99%). Next, a genome-wide microarray analysis of cocultured vs. monocultured hematopoietic SC derived from three independent experiments was performed. The analysis of differentially expressed genes was focused on products that are secretable and/or membrane-bound and potentially involved in antiapoptotic signalling.ResultsWe found CCL-12, Macrophage Inhibitory Factor, Fibronectin and connexin 40 significantly upregulated in our coculture model. An ELISA of cell culture supernatants was performed to confirm secretion of candidate genes and showed that coculture supernatants revealed markedly higher CCL-12 concentrations. Moreover, we stimulated NRVCM with concentrated coculture supernatants which resulted in a significant reduction of apoptosis compared to monoculture-derived supernatant. Mechanistically, NRVCMs stimulated with coculture supernatants showed a higher level of AKT-phosphorylation, consistent with enhanced antiapoptotic signaling.ConclusionIn summary, our results show that the interaction between hematopoietic SC and NRVCM led to a modified gene expression and induction of antiapoptotic pathways. These findings may thus at least in part explain the cardioprotective effects of hematopoietic SC.

【 授权许可】

Unknown   
© Rosenberg et al.; licensee BioMed Central Ltd. 2012. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.