Reduced Collagen Deposition in Infarcted Myocardium Facilitates Induced Pluripotent Stem Cell Engraftment and Angiomyogenesis for Improvement of Left Ventricular Function

Abstract

Objectives The purpose of this study was to assess the effect of scar tissue composition on engraftment of progenitor cells into infarcted myocardium. Background Scar tissue formation after myocardial infarction creates a barrier that severely compromises tissue regeneration, limiting potential functional recovery. Methods In vitro: A tricell patch (Tri-P) was created from peritoneum seeded and cultured with induced pluripotent stem cell–derived cardiomyocytes, endothelial cells, and mouse embryonic fibroblasts. The expression of fibrosis-related molecules from mouse embryonic fibroblasts and infarcted heart was measured by Western blot and quantitative reverse transcriptase polymerase chain reaction. In vivo: A Tri-P was affixed over the entire infarcted area 7 days after myocardial infarction in mice overexpressing adenylyl cyclase 6 (AC6). Engraftment efficiency of progenitor cells in hearts of AC6 mice was compared with that of control wild-type (WT) mice using a combination of in vivo bioluminescence imaging, post-mortem ex vivo tissue analysis, and the number of green fluorescent protein–positive cells. Echocardiography of left ventricular (LV) function was performed weekly. Hearts were harvested for analysis 4 weeks after Tri-P application. Mouse embryonic fibroblasts were stimulated with forskolin before an anoxia/reoxygenation protocol. Fibrosis-related molecules were analyzed. Results In AC6 mice, infarcted hearts treated with Tri-P showed significantly higher bioluminescence imaging intensity and numbers of green fluorescent protein–positive cells than in WT mice. LV function improved progressively in AC6 mice from weeks 2 to 4 and was associated with reduced LV fibrosis. Conclusions Application of a Tri-P in AC6 mice resulted in significantly higher induced pluripotent stem cell engraftment accompanied by angiomyogenesis in the infarcted area and improvement in LV function.

Myocardial Reprogramming Medicine: The Development, Application, and Challenge of Induced Pluripotent Stem Cells

“…A cardiac tissue sheet reassembled with defined cardiovascular populations (including purified hiPSC-derived cardiomyocytes and New Journal of Science ECs) was implanted in an animal MI model which showed significant and sustained improvement of cardiac function accompanied by neovascularization [193,194]. In our studies, a tricell omentum patch (seeded with iPSC-derived cardiomyocytes, ECs, and MEFs) was created and implanted into mice resulting in significantly higher cell engraftment accompanied by angiomyogenesis in the infarcted area and improvement in heart function [195,196]. The combination of cell sheet and the omentum flap has emerged as a promising iPSC technique for the development of tissue-engineered vascular-rich new myocardium in vivo [197].…”

“…This problem can be improved by morphological selection, label or staining strategies using fluorescence activated cell sorters (FACS), and drug selection approaches [247][248][249]. For instance, after defined differentiation induction of iPSCs, our previous studies used FACS to isolated CD31 positive derived ECs and purified NCX1 positive derived cardiomyocytes by puromycin resistance selection [195,196]. NKX2-5 positive cardiomyocytes from iPSCs were purified by FACS and survived upon transplantation into the infarcted mouse heart without formation of teratomas [250].…”

Suicide Gene-Mediated Sequencing Ablation Revealed the Potential Therapeutic Mechanism of Induced Pluripotent Stem Cell-Derived Cardiovascular Cell Patch Post-Myocardial Infarction

“…Recent studies have shown that induced pluripotent stem cells (iPSC) may have therapeutic potential (13). Experimental studies in animals have yielded encouraging results when iPSC are transplanted into peri-infarction myocardial zones (4). Treatments with iPSC appear to result in an improvement in cardiac contractile function (4), but numerous questions remain unanswered with regard to the use of such cells as therapy for post-MI repair.…”

“…It has been confirmed that PCs secrete cytokines, chemokines, and growth factors that could potentially promote repair of injured cardiac tissue (10). Two mechanisms have been suggested by which cardiac repair after an ischemic insult can occur: (i) PC differentiation directed toward a coordinated generation of new cardiac muscle cells and accompanying establishment of a new or expanded microcirculation (7) and (ii) PC secretions of paracrine factors, including cytokines, chemokines, and growth factors that alone or in combination recruit new reparative cells to the injury area and promote and support in situ tissue repair process (4,7,10,13). The latter paracrine mechanism could potentially provide for a noncell-based alternative to the PC use in treatment of cardiovascular disease (18).…”

“…Certainly, delivery of a paracrine agent might be preferable to cellbased therapies, as such molecular entities are generally easier to produce and could be safer as they cannot replicate or differentiate. However, since iPSC can be programmed to differentiate directly into specific and desired cardiovascular cell lineages, these cell-based approaches have recently gained interest as potential therapeutic treatments (4,12).…”