Bioenergetic and Functional Consequences of Cellular Therapy

Abstract

Rationale The mechanism by which endogenous progenitor cells contribute to functional and beneficial effects in stem cell therapy remains unknown. Objective Utilizing a novel 31P 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. Methods and 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 31P 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.

Autologous Mesenchymal Stem Cells Produce Concordant Improvements in Regional Function, Tissue Perfusion, and Fibrotic Burden When Administered to Patients Undergoing Coronary Artery Bypass Grafting

“…From preclinical and translational studies in an acute or subacute ischemic environment, it is known that MSCs act in a multifactorial manner 36-39 . MSCs release anti-fibrotic matrix metaloproteases, modulate cardiac stem cell proliferation and differentiation 9 , stimulate neovascularization 17, 2240 , establish intercellular coupling with cardiomyocytes 41 , mediate Akt-dependant change in calcium and upregulate C×43 42 .…”

Myocardial ATP hydrolysis rates in vivo: a porcine model of pressure overload-induced hypertrophy

“…Assessments were performed on a 1.5-Tesla clinical scanner (Siemens Sontata, Siemens Medical Systems, Islen, NJ) with a phased-array four-channel surface coil and ECG gating (20). Cardiac MRI was performed 1 day before the terminal open chest NMR studies were carried out.…”

“…Myocardial blood flow was assessed via first-pass perfusion MRI and quantified with automated software (CIMRA; CSON Medical, Minneapolis, MN), as previously described (7,20). Upon completion of the final set of in vivo magnetic resonance (MR) experiments, the results from first-pass perfusion MRI were corroborated via the injection of fluorescently labeled microspheres, as previously described (21).…”

Myocardial cell sheet therapy and cardiac function

“…Fibrin patches with mesenchymal stem cells (MSCs) or hESC-derived vascular cells have been successfully used in MCT (49,106). Itabashi and colleagues (27) developed a novel and simple method for a functional MCS using thin, biodegradable, polymerized fibrin-coated dishes.…”

“…The inflammation and secreted cytokines induced by the transplanted cells stimulate host tissues to promote neovascularization and the differentiation of cardiac progenitors. The transplantation of fibrin patch with hESCs-vascular cells was reported to recruit endogenous CPCs effectively (106). Endogenous CPCs can contribute to the improvement of cardiac function in MCS therapy, especially with fibrin-based MCSs.…”