Reconstitute the damaged heart via the dual reparative roles of pericardial adipose-derived flk-1+ stem cells

• Published in: International journal of cardiology 2016-01, Vol.202, p.256-264
• Main Authors: Wang, Xiaoming, Liu, Xueqing, Zhang, Hui, Nie, Liangming, Chen, Min, Ding, Zhaoping
• Format: Article
• Language: English
• Subjects: Adipocytes - cytology; Adipocytes - metabolism; Adipose-derived stromal cells; Animals; Cardiovascular; Cell Differentiation; Cells, Cultured; Disease Models, Animal; flk-1; Flow Cytometry; Immunohistochemistry; Male; Microvasculature; Myocardial Infarction - therapy; Myogenesis; Pericardial; Pericardium - cytology; Pericardium - metabolism; Rats; Rats, Wistar; Stem Cell Transplantation - methods; Stem Cells - cytology; Stem Cells - metabolism; Vascular Endothelial Growth Factor Receptor-2 - metabolism; Vasculogenesis
• ISSN: 0167-5273; 1874-1754
• DOI: 10.1016/j.ijcard.2015.09.002

Abstract Background The pericardial adipose derived stromal cells (pADSC) own a developmental origin from the “second heart field” and thus favor myogenic differentiation. The present experiments extended our previous observation by defining a subset of pADSC marked with the expression of flk-1, a type II receptor for VEGF to efficiently enhance cardiac repair. Methods and results Immunofluorescence and flow cytometry showed that flk-1 positive cells represented about 12% in the pericardial tissue and the total isolated pADSC. The purified flk-1 positive pADSC by magnetic sorting (flk-1pos pADSC) show the ability of forming spherical structure in which both myogenic (cTnT+ ) and angiogenic (vWF+ ) precursors were concurrently generated in culture. After being intramyocardially transplanted into the ischemic hearts, flk-1pos pADSC yielded superior structural repair to PBS control or flk-1neg pADSC, characterized by the thickening of the infarcted wall in which both myogenesis and angiogenesis of microvasculature (preferentially with ϕ < 50 μm) were significantly ensured ( p < 0.01). The structure benefits were also translated into a functional restoration 28 days after transplantation (EF = 44% vs. 62%, p < 0.01). Further pulse-chase labeling experiments with BrdU revealed that neomyogenesis and neoangiogenesis contribute in the structural repair. The newly formed myocardium was resulted from the proliferation of pre-existing cardiomyocytes that re-entered cell cycle (ki-67 positive). Conclusion Flk-1pos pADSC are capable of concurrently giving rise to both myogenic and angiogenic precursors in vitro and, after transplantation in vivo , to reconstitute the damaged heart by the neoformation of microvasculature and of cardiomyocytes and thus represent an attracting donor cells for stem cell-based therapy.