Concise Review: Reduction of Adverse Cardiac Scarring Facilitates Pluripotent Stem Cell-Based Therapy for Myocardial Infarction

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  Figure 1. Strategies to improve survival and engraftment of implanted cells. Poor cell engraftment remains a major challenge for stem cell‐based therapies such as use of pluripotent stem cells derived cardiovascular cells. Before cell implantation or delivery, there are various strategies available to evoke an adaptation and increased resistance to the hypoxic stimulus, including physical or chemical preconditioning, genetic manipulation, and use of biomaterial in tissue engineering to prevent cell damage. After implantation in an extremely low oxygen and nutrient ischemic environment, the graft cell survival will be challenged by pro‐apoptotic reactive oxygen species, proteolytic enzymes, and pro‐inflammatory or cytotoxic cytokines released from the damaged host heart tissue. And graft cell migration will be further limited by the excessive deposition of collagen matrix from fibrotic response. Accordingly, there are several strategies targeting the host environment in order to enhance cell engraftment and functional integration. Abbreviations: ROS, reactive oxygen species; PSC‐CVC, pluripotent stem cells derived cardiovascular cells.

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  Figure 2. Potential interactions between fibrotic tissue and implanted cells. (A): Representative Masson's trichrome imaging of myocardial scar tissue at 1‐week postinfarction. Following infarct healing, damaged myocardium is rapidly replaced by fibrotic tissue composed of fibroblasts and collagens. Implanted cells (either epicardial or intramyocardial delivery) invade in fibrotic tissue through production of paracrine factors to degrade fibrillar collagens. Conversely, multiple factors, such as fragments of extracellular matrix, pro‐inflammatory cytokines, and mechanical signals, derived from fibrotic tissue can obstruct the migration and engraftment of implanted cells. Scale bar = 50 μm. (B): During post‐MI inflammatory phase, the survival and function of implanted cells is repressed by multiple pro‐inflammatory factors. During the overactive reparative or proliferative phase, the electrophysiological activity of implanted cardiomyocytes would be interrupted by the myofibroblasts through gap junction or mechanical coupling. During the maturation phase, the increased tissue stiffness would inhibit the contractile function of implanted cardiomyocytes through mechanotransduction signaling.…

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  Figure 3. Overview of antifibrotic approaches to enhance stem cell‐based regeneration. An antifibrotic strategy targeting the fibrogenic signaling (such as TGF) and collagen deposition can be applied to enhance the engraftment of implanted stem cells or pluripotent stem cell‐derived cardiac cells. Multiple approaches such as using pharmacological agents, gene therapy, microRNA mimics, and modified biomaterials are exemplified. Abbreviations: TGF, transforming growth factor; AC6, adenylyl cyclase‐6; TSP2, thrombospondin‐2.

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  Figure 4. Overexpression of AC6 facilitates cell engraftment of induced pluripotent stem cell (iPSC)‐derived patches. (A): In vivo engraftment of iPSC‐derived cardiac cell patches in WT or AC6 transgenic mice was tracked by bioluminescent imaging assay at 4 weeks after surgery. A stronger cell engraftment signal was observed in AC6 mice as compared with WT mice. WT mice were implanted with cell patch without reporter gene as a background control. (B): Heart sections at 4 weeks after cell patch transplantation stained with Masson's trichrome and quantification of the percentage of LV fibrotic area. (C): M‐mode echocardiograms in WT or AC6 mice implanted with cell patch. Quantitative data of EF up to 4 weeks after surgery. Abbreviations: AC6, adenylyl cyclase‐6; WT, wild‐type; LV, left ventricular; EF, ejection fraction (reprinted with permission from Dai et al. J Am Coll Cardiol 2011;58:2118).

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  Figure 5. Use of miR‐29 mimic facilitates cell migration and vascularization of induced pluripotent stem cell (iPSC)‐derived patches. (A): Migration of iPSC‐derived cells labeled by GFP (green) in infarct zone was enhanced after administration of miR‐29 mimic in myocardial infarction (MI) mice. Viable cardiomyocytes derived from iPSC (yellow) or host origin (red) were identified by staining of cardiac troponin T (cTnT). Scale bars = 100 μm. (B): Perfusion of contrast agents in micro‐CT imaging indicates the cardiac collateral vessel networks of MI mice that were treated with miR‐29 mimic or negative control during cell implantation. The dotted line shows the location of cell patch (reprinted with permission from Huang et al. PLoS One 2013;8:e70023).