Advances in the Generation of Constructed Cardiac Tissue Derived from Induced Pluripotent Stem Cells for Disease Modeling and Therapeutic Discovery

Abstract

The human heart lacks significant regenerative capacity; thus, the solution to heart failure (HF) remains organ donation, requiring surgery and immunosuppression. The demand for constructed cardiac tissues (CCTs) to model and treat disease continues to grow. Recent advances in induced pluripotent stem cell (iPSC) manipulation, CRISPR gene editing, and 3D tissue culture have enabled a boom in iPSC-derived CCTs (iPSC-CCTs) with diverse cell types and architecture. Compared with 2D-cultured cells, iPSC-CCTs better recapitulate heart biology, demonstrating the potential to advance organ modeling, drug discovery, and regenerative medicine, though iPSC-CCTs could benefit from better methods to faithfully mimic heart physiology and electrophysiology. Here, we summarize advances in iPSC-CCTs and future developments in the vascularization, immunization, and maturation of iPSC-CCTs for study and therapy.

Differentiation of Pluripotent Stem Cells for Disease Modeling: Learning from Heart Development

“…The tightly adjoined mosaic cells of the heart’s epicardium and endocardium undergo signaling which initiates a transition to a plastic mesenchymal phenotype, becoming multiple other cell types. The epithelial cells of the epicardium produce cardiac fibroblasts, mural cells (vascular smooth muscle and pericytes), and some endothelial cells [ 27 ]. The endothelial cells of the endocardium can undergo a more transient transition to a mesenchymal phenotype to enable migration and the formation of new structures like the valves of the heart [ 28 ], endocardial cushioning, and coronary vasculature [ 29 ].…”

“…While EMT in the endocardium contributes to the formation of the heart’s internal architecture, dysregulated EMT later in life can contribute to valvular and vascular disease [ 29 ]. EMT is regulated by several signaling pathways including TGF-β/BMP, VEGF, FGF, PDGF, and Wnt/β-catenin, which also play vital roles in other aspects of cardiogenesis [ 27 , 29 ]. Inflammatory stimulation by TNF, IFN, IL-1B, proteases, and hypoxia can also contribute to EMT [ 28 , 29 ].…”

“…It has been noted that the secretion of EVs to facilitate crosstalk between cell types is mechanistically significant, and its further investigation may enable more fine-tuned control over cardiac organoids and spheroids [ 31 ]. EVs obtained from patients’ healthy, diseased, or otherwise stimuli-conditioned tissue may even be used to establish particular phenotypes in cardiovascular models or patients [ 27 , 31 , 32 , 182 , 183 ]. Giacomelli et al induced the cardiac mesoderm in a monolayer culture by activating Wnt/β-catenin and TGF-β signaling using CHIR99021, Activin, and BMP4.…”

“…While cardiac organoids and spheroids may be manipulated by the introduction of specific EVs, EVs may also be harvested from patients or cardiac tissues to be used as potential therapeutics [ 27 , 182 , 183 ]. Recently, a combination of studies investigating cardiac EVs from healthy patients versus those from patients exposed to remote/non-cardiac ischemia were performed.…”

“…Similarly, tumor-derived EVs promote a premetastatic niche [ 31 ]. In fact, exosomes, a type of EV, have been loaded into cardiac patches in recent clinical trials, and have even been harvested from in vitro cardiac tissues including cardiac organoids and spheroids [ 27 , 32 ]. Life-like cardiac organoids and spheroids provide a well-suited platform to study both the production and impacts of EVs on signaling pathways.…”