Abstract
Cell therapies are extensively tested to restore heart function after myocardial infarction (MI). Survival of any cell type after intracardiac administration, however, may be limited due to unfavorable conditions of damaged tissue. Therefore, the aim of this study was to evaluate the therapeutic effect of adipose-derived stromal cells (ADSCs) and human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) overexpressing either the proangiogenic SDF-1α or anti-inflammatory heme oxygenase-1 (HO-1) in a murine model of MI. ADSCs and hiPSCs were transduced with lentiviral vectors encoding luciferase (Luc), GFP and either HO-1 or SDF-1α. hiPSCs were then differentiated to hiPSC-CMs using small molecules modulating the WNT pathway. Genetically modified ADSCs were firstly administered via intracardiac injection after MI induction in Nude mice. Next, ADSCs-Luc-GFP and genetically modified hiPSC-CMs were injected into the hearts of the more receptive NOD/SCID strain to compare the therapeutic effect of both cell types. Ultrasonography, performed on days 7, 14, 28 and 42, revealed a significant decrease of left ventricular ejection fraction (LVEF) in all MI-induced groups. No improvement of LVEF was observed in ADSC-treated Nude and NOD/SCID mice. In contrast, administration of hiPSC-CMs resulted in a substantial increase of LVEF, occurring between 28 and 42 days after MI, and decreased fibrosis, regardless of genetic modification. Importantly, bioluminescence analysis, as well as immunofluorescent staining, confirmed the presence of hiPSC-CMs in murine tissue. Interestingly, the luminescence signal was strongest in hearts treated with hiPSC-CMs overexpressing HO-1. Performed experiments demonstrate that hiPSC-CMs, unlike ADSCs, are effective in improving heart function after MI. Additionally, long-term evaluation of heart function seems to be crucial for proper assessment of the effect of cell administration.
Highlights
The adult human heart has a minimal ability to regenerate, and the loss of viable cardiomyocytes in coronary heart disease, accelerated by myocardial infarction (MI), frequently leads to heart failure (HF)
The goal of this study was to verify the claimed, but not really proven, regenerative potential of adipose stromal cells in the injured heart and to determine whether the suggested therapeutic effect of hiPSC-CMs can be improved by overexpression of cardioprotective, proangiogenic and immunomodulatory factors, namely heme oxygenase-1 (HO-1) and SDF-1α
Standard molecular cloning allowed for the introduction of HMOX1 and CXCL12 coding sequences upstream of SFFV cloning promoter (Figure parallel, adipose-derived stromal cells (ADSCs) were isolated fromcoding liposuction standard molecular allowed for1a)
Summary
The adult human heart has a minimal ability to regenerate, and the loss of viable cardiomyocytes in coronary heart disease, accelerated by myocardial infarction (MI), frequently leads to heart failure (HF). Bergmann et al reported that cardiomyocyte renewal in physiological conditions in humans is as little as 1% of cells renewed per year at the age of 20 and further drops to 0.4% at the age of 75 [1]. This rate can increase upon myocardial damage; no more than 3% of cardiomyocytes located near the injury region activate cell division, which is far too little for meaningful regeneration [2]. There is an immense need for novel therapies, which would allow for the recovery of viable myocardium in the injured site
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