Therapy with mesenchymal stromal cells or conditioned medium reverse cardiac alterations in a high-fat diet–induced obesity model P.S. DALTRO 1,2 , B.C. BARRETO 1,3 , P.G. SILVA 4 , P. CHENAUD NETO 4 , P.H.F. SOUSA FILHO 4 , D. SANTANA NETA 4 , G.B. CARVALHO 1 , D.N. SILVA 1 , B.D. PAREDES 1 , A.C. DE ALCANTARA 1 , L.A.R. FREITAS 4,5 , R.D. COUTO 6 , R.R. SANTOS 1,7 , B.S.F. SOUZA 1,5,7 , M.B.P. SOARES 1,5,7 & S.G. MACAMBIRA 1,5,7,8 1 Center for Biotechnology and CellTherapy, Salvador, BA, Brazil, 2 Multicentric Program in Biochemistry and Molecular Biology, Federal University of Bahia, Salvador, BA, Brazil, 3 Faculty of Biology,Federal University of Bahia, Salvador, BA, Brazil, 4 Faculty of Medicine, Federal University of Bahia, Salvador, BA, Brazil, 5 Gonçalo Moniz Institute, Oswaldo Cruz Foundation (FIOCRUZ), Salvador, BA, Brazil, 6 Faculty of Pharmacy, Federal University of Bahia, Salvador, BA, Brazil, 7 National Institute of Science andTechnology for Regenerative Medicine, Rio de Janeiro, RJ, Brazil, and 8 Department of Biochemistry and Biophysics, Institute of Health Sciences, Federal University of Bahia, Salvador, BA, Brazil Abstract Background. Obesity is associated with numerous cardiac complications, including arrhythmias, cardiac fibrosis, remodel- ing and heart failure. Here we evaluated the therapeutic potential of mesenchymal stromal cells (MSCs) and their conditioned medium (CM) to treat cardiac complications in a mouse model of high-fat diet (HFD)–induced obesity. Methods. After obesity induction and HFD withdrawal, obese mice were treated with MSCs, CM or vehicle. Cardiac function was as- sessed using electrocardiography, echocardiography and treadmill test. Body weight and biochemical parameters were evaluated. Cardiac tissue was used for real time (RT)-polymerase chain reaction (PCR) and histopathologic analysis. Results/ Discussion. Characterization of CM by protein array showed the presence of different cytokines and growth factors, including chemokines, osteopontin, cystatin C, Serpin E1 and Gas 6. HFD-fed mice presented cardiac arrhythmias, altered cardiac gene expression and fibrosis reflected in physical exercise incapacity associated with obesity and diabetes. Administration of MSCs or CM improved arrhythmias and exercise capacity.This functional improvement correlated with normalization of GATA4 gene expression in the hearts of MSC- or CM-treated mice.The gene expression of connexin 43, troponin I, adiponectin, transforming growth factor (TGF) β, peroxisome proliferator activated receptor gamma (PPARγ), insulin-like growth factor 1 (IGF-1), matrix metalloproteinase-9 (MMP9) and tissue inhibitor of metalloproteinases 1 (TIMP1) were significantly reduced in MSCs, but not in CM-treated mice. Moreover, MSC or CM administration reduced the intensity of cardiac fibrosis. Conclusion. Our results suggest that MSCs and CM have a recovery effect on cardiac disturbances due to obesity and corroborate to the paracrine action of MSCs in heart disease models. Key Words: cardiac dysfunction, cell therapy, mesenchymal stromal cells, obesity Introduction Obesity and excessive consumption of dietary fats have deleterious consequences to the metabolism and heart function, being strongly linked to the progression of type 2 diabetes mellitus (DM2) and heart disease [1,2]. Obesity has been associated with structural and func- tional changes in the heart, including arrhythmias, cardiac fibrosis and subclinical impairment of left ven- tricle systolic and diastolic functions. Some cardiac alterations associated with structural and electrical re- modeling are irreversible and can lead to heart failure, increasing the risk for sudden death through mecha- nisms that are not completely elucidated [3]. In addition to the electrical remodeling and severe arrhythmias, long-standing obesity is also as- sociated with structural remodeling, characterized by eccentric hypertrophy and followed by diastolic dysfunction and fibrosis, despite coronary disease or hypertension [4–6].When isolated from other cardiac Correspondence: Simone Garcia Macambira, PhD, Department of Biochemistry and Biophysics, Institute of Health Sciences, Federal University of Bahia, Av. Reitor Miguel Calmon s/n—Vale do Canela, Salvador, BA 40.110-100, Brazil. E-mail: simonegm@ufba.br (Received 15 March 2017; accepted 4 July 2017) ISSN 1465-3249 Copyright © 2017 International Society for Cellular Therapy. Published by Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.jcyt.2017.07.002 Cytotherapy, 2017; 19: 1176–1188