Stem cell activation sustains hereditary hypertrophy in hamster cardiomyopathy

• Published in: The Journal of pathology 2005-02, Vol.205 (3), p.397-407
• Main Authors: Fiaccavento, Roberta, Carotenuto, Felicia, Minieri, Marilena, Fantini, Cristina, Forte, Giancarlo, Carbone, Arnaldo, Carosella, Luciana, Bei, Roberto, Masuelli, Laura, Palumbo, Camilla, Modesti, Andrea, Prat, Maria, Di Nardo, Paolo
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis; Biological and medical sciences; Capillaries - pathology; Cardiology. Vascular system; cardiomyopathy; Cardiomyopathy, Hypertrophic, Familial - metabolism; Cardiomyopathy, Hypertrophic, Familial - pathology; Cell Differentiation - drug effects; Cell Division; Cells, Cultured; Cricetinae; cytokines; Endothelium, Vascular - pathology; Heart; Heart Ventricles - ultrastructure; Hepatocyte Growth Factor - blood; Hepatocyte Growth Factor - metabolism; Hepatocyte Growth Factor - pharmacology; Investigative techniques, diagnostic techniques (general aspects); Medical sciences; Mesenchymal Stromal Cells - drug effects; Mesenchymal Stromal Cells - pathology; Myocarditis. Cardiomyopathies; myocyte; Myocytes, Cardiac - ultrastructure; Pathology. Cytology. Biochemistry. Spectrometry. Miscellaneous investigative techniques; stem cells
• ISSN: 0022-3417; 1096-9896
• DOI: 10.1002/path.1717

Recent studies have documented the presence of stem cells within the myocardium and their role in the repair of ischaemic injury. Nevertheless, the pathogenic role of stem cells in non‐ischaemic myocardial diseases, as well as the factors potentially responsible for their activation, is still under debate. The present study demonstrates the presence of an increased number of c‐kit positive, MDR‐positive, and Sca‐1‐positive stem cells within the myocardium of hereditary δ‐SG null hamsters, a spontaneously occurring model of hypertrophic cardiomyopathy. When hamsters are 80 days old, ie at the ‘hypertrophic’ stage of the disease, but without haemodynamic overload, these cells associate with a multitude of cells co‐expressing c‐kit, cMet, GATA4, or MEF‐2, and proliferating myocytes co‐expressing myosin heavy chain, telomerase, ki67 and cyclin B. Furthermore, at the same animal age, the number of myocardial cells co‐expressing c‐kit and Flk‐1, and the number of capillary vessels, is also amplified. In order to identify factors potentially responsible for stem cell activation, the myocardial expression of HGF and cMet and HGF plasma levels were evaluated, demonstrating their increase in 80‐day‐old δ‐SG null hamsters. To demonstrate the possible ability of HGF to induce stem cell differentiation, bone‐marrow‐derived mesenchymal stem cells were challenged with HGF at the same plasma concentration observed in vivo. HGF induced cMet phosphorylation, and caused loss of stem cell features and overexpression of MEF‐2, TEF1, and MHC. Our results demonstrate that stem cell activation occurs within the cardiomyopathic myocardium, very likely to maintain an efficient cardiac architecture. In this context, elevated levels of HGF might play a role in induction of stem cell commitment to the cardiomyocyte lineage and in cardioprotection through its anti‐apoptotic action. Consistently, when cytokine levels declined to physiological concentrations, as in 150‐day‐old cardiomyopathic animals, myocardial apoptosis prevailed, prejudicing cardiac function. Copyright © 2005 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.