Therapy with mesenchymal stromal cells or conditioned medium reverse cardiac alterations in a high-fat diet–induced obesity model

Obesity is associated with numerous cardiac complications, including arrhythmias, cardiac fibrosis, remodeling 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-...

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Published in:	Cytotherapy (Oxford, England) Vol. 19; no. 10; pp. 1176 - 1188
Main Authors:	Daltro, P.S., Barreto, B.C., Silva, P.G., Neto, P. Chenaud, Sousa Filho, P.H.F., Santana Neta, D., Carvalho, G.B., Silva, D.N., Paredes, B.D., de Alcantara, A.C., Freitas, L.A.R., Couto, R.D., Santos, R.R., Souza, B.S.F., Soares, M.B.P., Macambira, S.G.
Format:	Journal Article
Language:	English
Published:	England Elsevier Inc 01-10-2017
Subjects:	Animals Arrhythmias, Cardiac - etiology Arrhythmias, Cardiac - therapy cardiac dysfunction cell therapy Culture Media, Conditioned - pharmacology Cytokines - metabolism Diet, High-Fat - adverse effects Fibrosis - genetics Fibrosis - pathology GATA4 Transcription Factor - genetics Gene Expression - drug effects Heart - drug effects Heart - physiopathology Intercellular Signaling Peptides and Proteins - metabolism Male Mesenchymal Stem Cell Transplantation - methods mesenchymal stromal cells Mesenchymal Stromal Cells - cytology Mesenchymal Stromal Cells - physiology Mice, Inbred BALB C Myocardium - pathology obesity Obesity - etiology Obesity - physiopathology cardiac dysfunction cell therapy obesity mesenchymal stromal cells
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Summary:	Obesity is associated with numerous cardiac complications, including arrhythmias, cardiac fibrosis, remodeling 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. After obesity induction and HFD withdrawal, obese mice were treated with MSCs, CM or vehicle. Cardiac function was assessed 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. 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. 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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1465-3249 1477-2566
DOI:	10.1016/j.jcyt.2017.07.002