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

Abstract

Pluripotent stem cells (PSCs) are an attractive, reliable source for generating functional cardiomyocytes for regeneration of infarcted heart. However, inefficient cell engraftment into host tissue remains a notable challenge to therapeutic success due to mechanical damage or relatively inhospitable microenvironment. Evidence has shown that excessively formed scar tissues around cell delivery sites present as mechanical and biological barriers that inhibit migration and engraftment of implanted cells. In this review, we focus on the functional responses of stem cells and cardiomyocytes during the process of cardiac fibrosis and scar formation. Survival, migration, contraction, and coupling function of implanted cells may be affected by matrix remodeling, inflammatory factors, altered tissue stiffness, and presence of electroactive myofibroblasts in the fibrotic microenvironment. Although paracrine factors from implanted cells can improve cardiac fibrosis, the transient effect is insufficient for complete repair of an infarcted heart. Furthermore, investigation of interactions between implanted cells and fibroblasts including myofibroblasts helps the identification of new targets to optimize the host substrate environment for facilitating cell engraftment and functional integration. Several antifibrotic approaches, including the use of pharmacological agents, gene therapies, microRNAs, and modified biomaterials, can prevent progression of heart failure and have been developed as adjunct therapies for stem cell‐based regeneration. Investigation and optimization of new biomaterials is also required to enhance cell engraftment of engineered cardiac tissue and move PSCs from a laboratory setting into translational medicine.

Neurotrophin-3 contributes to benefits of human embryonic stem cell-derived cardiovascular progenitor cells against reperfused myocardial infarction

“…In this study, we showed that the improvement of cardiomyocyte survival and vascularization in the infarcted hearts by hCVPCs and hNT‐3 are associated with the better cardiac function and reduced fibrosis formation. This is consistent with previous reports showing that anti‐apoptosis/necrosis of cardiomyocytes and/or improvement of angiogenesis can significantly reduce scar size in MI or I/R hearts 54,55 . Because MI and I/R cause apoptosis/necrosis of cardiomyocytes and destroy capillary networks, to rebuild vascular network after MI or I/R is essential for delivering oxygen and metabolites to cardiac cells to help recovery of damaged cells and thereby links to reduce scar size 1,54,56‐58 .…”

In situmaturated early-stage human induced pluripotent stem cell-derived cardiomyocytes improve cardiac function by enhancing segmentary contraction in infarcted rats

“…rising number of pluripotent stem-cell-based therapies to treat myocardial infarction have been proposed. However, only marginal improvements in cardiac function have been reported from rodents to large animal models[47][48][49]. Here, we demonstrated (1) that the intramyocardial injection of 10 million early-stage hiPSC-CMs seven days after MI improved LV segmentary performance on infarcted rats.…”

Roles of Reactive Oxygen Species in Cardiac Differentiation, Reprogramming, and Regenerative Therapies

“…Understanding of the healing process of MI, including inflammatory, proliferative, and maturation phases, is important for design and timing selection of cell transplantation in patients. There exists a potential feedback loop (cell-cell interaction) between the host infarcted myocardium and the engraftment of implanted cells, as discussed by us [124]. In this section, we integrate the current evidence to speculate how ROS affect the cell survival and functional engraftment of implanted or regenerated CMs in the infarcted heart (Figure 3).…”