Human microvascular pericytes (CD146+/34−/45−/56−) contain multipotent precursors and repair/regenerate defective tissues, notably skeletal muscle. However, their ability to repair the ischemic heart remains unknown. We investigated the therapeutic potential of human pericytes, purified from skeletal muscle, for treating ischemic heart disease and mediating associated repair mechanisms in mice. Echocardiography revealed that pericyte transplantation attenuated left ventricular dilatation and significantly improved cardiac contractility, superior to CD56+ myogenic progenitor transplantation, in acutely infarcted mouse hearts. Pericyte treatment substantially reduced myocardial fibrosis and significantly diminished infiltration of host inflammatory cells at the infarct site. Hypoxic pericyte-conditioned medium suppressed murine fibroblast proliferation and inhibited macrophage proliferation in vitro. High expression by pericytes of immunoregulatory molecules, including IL-6, LIF, COX-2 and HMOX-1, was sustained under hypoxia, except for MCP-1. Host angiogenesis was significantly increased. Pericytes supported microvascular structures in vivo and formed capillary-like networks with/without endothelial cells in three-dimensional co-cultures. Under hypoxia, pericytes dramatically increased expression of VEGF-A, PDGF-β, TGF-β1 and corresponding receptors while expression of bFGF, HGF, EGF, and Ang-1 was repressed. The capacity of pericytes to differentiate into and/or fuse with cardiac cells was revealed by GFP-labeling, though to a minor extent. In conclusion, intramyocardial transplantation of purified human pericytes promotes functional and structural recovery, attributable to multiple mechanisms involving paracrine effects and cellular interactions.

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Implantation of three- and five-layered myoblast sheets yields favorable results, with better improvement of cardiac function, induction of angiogenesis, more elastic fibers, and less fibrosis. Thus, layered myoblast sheets, in optimal numbers, may attenuate adverse cardiac remodeling of the infarcted heart.

Adipose tissue-derived mesenchymal stem cells (ADMSCs) are multipotent cells. Here we examined whether human ADMSCs (hADMSCs) could differentiate into cardiomyoblast-like cells (CLCs) by induction with dimethylsulfoxide and whether the cells would be utilized to treat cardiac dysfunction. Dimethylsulfoxide induced the expression of various cardiac markers in hADMSCs, such as alpha-cardiac actin, cardiac myosin light chain, and myosin heavy chain; none of which were detected in noncommitted hADMSCs. The induced cells were thus designated as hADMSC-derived CLCs (hCLCs). To confirm their beneficial effect on cardiac function, hCLC patches were transplanted onto the Nude rat myocardial infarction model, and compared with noncommitted hADMSC patch transplants and sham operations. Echocardiography demonstrated significant short-term improvement of cardiac function in both the patch-transplanted groups. However, long-term follow-up showed rescue and maintenance of cardiac function in the hCLC patch-transplanted group only, but not in the noncommitted hADMSC patch-transplanted animals. The hCLCs, but not the hADMSCs, engrafted into the scarred myocardium and differentiated into human cardiac troponin I-positive cells, and thus regarded as cardiomyocytes. Transplantation of the hCLC patches also resulted in recovery of cardiac function and improvement of long-term survival rate. Thus, transplantation of hCLC patches is a potentially effective therapeutic strategy for future cardiac tissue regeneration.

Tolvaptan can safely be used for CKD patients undergoing open-heart surgery and can provide a feasible urine volume without leading to a deterioration of their renal function.