Bioenergetic and functional consequences of cellular therapy: activation of endogenous cardiovascular progenitor cells.
BACKGROUND
The mechanism by which endogenous progenitor cells contribute to functional and beneficial effects in stem cell therapy remains unknown.


OBJECTIVE
Utilizing a novel (31)P magnetic resonance spectroscopy-2-dimensional chemical shift imaging method, this study examined the heterogeneity and bioenergetic consequences of postinfarction left ventricular (LV) remodeling and the mechanisms of endogenous progenitor cell contribution to the cellular therapy.


RESULTS
Human embryonic stem cell-derived vascular cells (hESC-VCs) that stably express green fluorescent protein and firefly luciferase (GFP(+)/Luc(+)) were used for the transplantation. hESC-VCs may release various cytokines to promote angiogenesis, prosurvival, and antiapoptotic effects. Both in vitro and in vivo experiments demonstrated that hESC-VCs effectively inhibit myocyte apoptosis. In the mouse model, a fibrin patch-based cell delivery resulted in a significantly better cell engraftment rate that was accompanied by a better ejection fraction. In the swine model of ischemia-reperfusion, the patch-enhanced delivery of hESC-VCs resulted in alleviation of abnormalities including border zone myocardial perfusion, contractile dysfunction, and LV wall stress. These results were also accompanied by a pronounced recruitment of endogenous c-kit(+) cells to the injury site. These improvements were directly associated with a remarkable improvement in myocardial energetics, as measured by a novel in vivo (31)P magnetic resonance spectroscopy-2-dimensional chemical shift imaging technology.


CONCLUSIONS
The findings of this study demonstrate that a severely abnormal heterogeneity of myocardial bioenergetics in hearts with postinfarction LV remodeling can be alleviated by the hESC-VCs therapy. These findings suggest an important therapeutic target of peri-scar border zone and a promising therapeutic potential for using hESC-VCs together with the fibrin patch-based delivery system.
Department of Medicine, University of Minnesota Medical School, Minneapolis, MN 55455, USA.
Qiang
Q
Xiong
Lei
L
Ye
Pengyuan
P
Zhang
Michael
M
Lepley
Cory
C
Swingen
Liying
L
Zhang
Dan S
DS
Kaufman
Jianyi
J
Zhang
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D002460:Cell Line; D002465:Cell Movement; D058948:Cell Tracking; D003326:Coronary Circulation; D004195:Disease Models, Animal; D053595:Embryonic Stem Cells / Q000378:metabolism / Q000637:transplantation*; D042783:Endothelial Cells / Q000378:metabolism / Q000637:transplantation*; D004734:Energy Metabolism; D005260:Female; D005337:Fibrin; D049452:Green Fluorescent Proteins / Q000096:biosynthesis / Q000235:genetics; D006801:Humans; D017379:Hypertrophy, Left Ventricular / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D049409:Luciferases, Firefly / Q000096:biosynthesis / Q000235:genetics; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009200:Myocardial Contraction; D009203:Myocardial Infarction / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000601:surgery*; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000378:metabolism / Q000637:transplantation*; D010725:Phosphocreatine / Q000378:metabolism; D019009:Proto-Oncogene Proteins c-kit / Q000378:metabolism; D020127:Recovery of Function; D033581:Stem Cell Transplantation / Q000379:methods; D013318:Stroke Volume; D013552:Swine; D013997:Time Factors; D054457:Tissue Scaffolds; D014162:Transfection; D016277:Ventricular Function, Left; D020257:Ventricular Remodeling
D010725:Phosphocreatine; D049452:Green Fluorescent Proteins; D000255:Adenosine Triphosphate; D005337:Fibrin; D049409:Luciferases, Firefly; D019009:Proto-Oncogene Proteins c-kit