Cardiomyogenesis Modeling Using Pluripotent Stem Cells: The Role of Microenvironmental Signaling

Abstract

Pluripotent stem cells (PSC) can be used as a model to study cardiomyogenic differentiation. In vitro modeling can reproduce cardiac development through modulation of some key signaling pathways. Therefore, many studies make use of this strategy to better understand cardiomyogenesis complexity and to determine possible ways to modulate cell fate. However, challenges remain regarding efficiency of differentiation protocols, cardiomyocyte (CM) maturation and therapeutic applications. Considering that the extracellular milieu is crucial for cellular behavior control, cardiac niche studies, such as those identifying secreted molecules from adult or neonatal tissues, allow the identification of extracellular factors that may contribute to CM differentiation and maturation. This review will focus on cardiomyogenesis modeling using PSC and the elements involved in cardiac microenvironmental signaling (the secretome – extracellular vesicles, extracellular matrix and soluble factors) that may contribute to CM specification and maturation.

The Cellular Stress Response Interactome and Extracellular Matrix Cross-Talk during Fibrosis: A Stressed Extra-Matrix Affair

“…Delineating the subtle mechanisms and cellular, molecular, and extracellular matrix players implicated in regenerative and non-regenerative hearts can provide insights into the homeostasisrepair-fibrosis continuum, which remains the most vexing challenge in developing successful regenerative/anti-fibrotic approaches for fibrotic disorders. Further, the refractory response of cardiomyocytes to complete cell-cycle progression through mitosis limits their self-renewal, therefore, cardiomyogenic approaches to treat heart failure remain practically intractable [38][39][40][41][42][43][44][45][46][47][48].…”

When Stiffness Matters: Mechanosensing in Heart Development and Disease

“…In order to generate in vitro cardiac-like tissue, either in the form of 3D construct or in the form of organoids, a combination of soluble (e.g., growth factors) and physical cues is necessary to form a fully mature and functional tissue. The soluble cues have been extensively studied (Paige et al, 2015;Denning et al, 2016;van den Berg et al, 2016;Leitolis et al, 2019), whereas the role of the physical cues is only recently been explored as a valuable approach to induce fully the maturation of the generated tissue (Lindsey et al, 2014). Despite great improvements in the differentiation of human pluripotent stem cell-derived CMs (hPSC-CMs) using a variety of approaches, the main limitation for the experimental use of these cells still remains their immature phenotype (Lieu et al, 2013).…”

Recapitulating Cardiac Structure and Function In Vitro from Simple to Complex Engineering

“…Various technologies, such as gene editing, cell assembly, 3D bioprinting, and computational modeling, have been employed to model such complexity [ 3 ]. The development of recent technologies integrating cardiac cells, biomaterials, and fabrication will help to advance cardiac tissue engineering [ 4 , 5 ]. Thus, it will be highly beneficial to understand the pros and cons of each technology, aiming at developing fully mature cardiac tissue.…”