The cardioprotective effect of mesenchymal stem cells is mediated by IGF-I and VEGF Sanga Sadat a,c, * ,1 , Sebastian Gehmert a,1 , Yao-Hua Song a , Yasheng Yen a , Xiaowen Bai a , Sebastian Gaiser b , Helmut Klein c , Eckhard Alt a, * a Department of Molecular Pathology, University of Texas, MD Anderson Cancer Center, Houston, TX 77030, USA b Department of Cancer Biology, University of Texas, MD Anderson Cancer Center, Houston, TX 77030, USA c Department of Cardiology, Angiology and Pneumology, Otto-von-Guericke University of Magdeburg, Magdeburg 39112, Germany Received 5 September 2007 Available online 24 September 2007 Abstract Emerging evidence suggests that adipose tissue-derived stem cells (ASCs) can be used for the treatment of ischemic heart diseases. However, the mechanisms underlying their therapeutic effects have not been clearly defined. In this study cytokines released by ASCs were detected by ELISA and pro-angiogenic effects were assessed by tube formation assay. To define the anti-apoptotic effect of ASCs, neonatal rat cardiomyocytes were subjected to hypoxia condition in a co-culture system. Our data show that ASCs secrete significant amounts of VEGF (810.65 ± 56.92 pg/lg DNA) and IGF-I (328.33 ± 22.7 pg/lg DNA). Cardiomyocytes apoptosis was significantly prevented by ASCs and 62.5% of the anti-apoptotic effect was mediated by IGF-I and 34.2% by VEGF. ASCs promoted endothelial cell tube formation by secreting VEGF. In conclusion we demonstrated that ASCs have a marked impact on anti-apoptosis and angi- ogenesis and helps to explain data of stem cells benefit without transdifferentiation. Ó 2007 Elsevier Inc. All rights reserved. Keywords: Adipose tissue-derived stem cells; Cardiomyocytes; Apoptosis; Angiogenesis; Cell therapy; Cytokines The concept of regenerative medicine using autologous stem cells to repair damaged tissue has emerged over the recent years [1]. Clinical trials suggest that stem cells may contribute to the healing of myocardial infarction (MI) [2–6]. Previous studies demonstrate that the beneficial effects are mediated by angiogenic and anti-apoptotic cyto- kines produced by mesenchymal stem cells [7]. Most of these studies have used bone marrow-derived or circulating blood-derived progenitor cells which are sometimes in lim- ited numbers and might require expansion. We and others have shown that adipose tissue also contains pluripotent mesenchymal stem cells which can be easily harvested and expanded in vitro [8–12]. Recent reports demonstrated that adipose tissue-derived stem cells (ASCs) produce sev- eral angiogenic factors such as HGF, VEGF, and bFGF [13,14]. However, the paracrine factors responsible for the anti-apoptotic effect have not been evaluated yet. Therefore the aim of the study was to examine the angio- genic and anti-apoptotic potential of ASC by investigating their ability to secrete VEGF and IGF-I. It was a further aim particularly to study the ability of ASC with regard to promotion of angiogenesis and prevention of apoptosis in cardiomyocytes at risk. Methods Cell culture Subcutaneous fat tissue was obtained from patient undergoing elective liposuction, which was in accordance with guidelines of the Declaration of Helsinki for biomedical research. ASCs were harvested, propagated, and characterized as described previously [15]. The multilineage differentiation 0006-291X/$ - see front matter Ó 2007 Elsevier Inc. All rights reserved. doi:10.1016/j.bbrc.2007.09.058 * Corresponding authors. Address: University of Texas, MD Anderson Cancer Center, SCRB2, Unit 951, 7435 Fannin Street, Houston, TX 77054, USA. Fax: +1 713 834 6103 (E. Alt). E-mail addresses: sanga.sadat@gmail.com (S. Sadat), ealtmd@aol.com (E. Alt). 1 These authors contributed equally to this work. www.elsevier.com/locate/ybbrc Biochemical and Biophysical Research Communications 363 (2007) 674–679