Many Cells Make Life Work—Multicellularity in Stem Cell-Based Cardiac Disease Modelling

Abstract

Cardiac disease causes 33% of deaths worldwide but our knowledge of disease progression is still very limited. In vitro models utilising and combining multiple, differentiated cell types have been used to recapitulate the range of myocardial microenvironments in an effort to delineate the mechanical, humoral, and electrical interactions that modulate the cardiac contractile function in health and the pathogenesis of human disease. However, due to limitations in isolating these cell types and changes in their structure and function in vitro, the field is now focused on the development and use of stem cell-derived cell types, most notably, human-induced pluripotent stem cell-derived CMs (hiPSC-CMs), in modelling the CM function in health and patient-specific diseases, allowing us to build on the findings from studies using animal and adult human CMs. It is becoming increasingly appreciated that communications between cardiomyocytes (CMs), the contractile cell of the heart, and the non-myocyte components of the heart not only regulate cardiac development and maintenance of health and adult CM functions, including the contractile state, but they also regulate remodelling in diseases, which may cause the chronic impairment of the contractile function of the myocardium, ultimately leading to heart failure. Within the myocardium, each CM is surrounded by an intricate network of cell types including endothelial cells, fibroblasts, vascular smooth muscle cells, sympathetic neurons, and resident macrophages, and the extracellular matrix (ECM), forming complex interactions, and models utilizing hiPSC-derived cell types offer a great opportunity to investigate these interactions further. In this review, we outline the historical and current state of disease modelling, focusing on the major milestones in the development of stem cell-derived cell types, and how this technology has contributed to our knowledge about the interactions between CMs and key non-myocyte components of the heart in health and disease, in particular, heart failure. Understanding where we stand in the field will be critical for stem cell-based applications, including the modelling of diseases that have complex multicellular dysfunctions.

Multiplexing physical stimulation on single human induced pluripotent stem cell-derived cardiomyocytes for phenotype modulation

“…Together, these results shed light on how fundamental developmental processes are regulated via multiple physical cues at the single cell level. We expect that this system will be applicable to other cell types where maturity and shape are similarly closely related and subsequently translated to multicellular in vitro models for developmental and clinical studies [5].…”

“…The recent discovery of human induced pluripotent stem cells (hiPSCs) and their ability to differentiate into CMs initially boosted hopes among clinicians and patients [3,4], as this might offer an attractive alternative to organ transplantation that could in principle supply an unlimited source of patient-specific CMs for personalized, regenerative medicine. However, full realization of the potential of hiPSC-CMs has been hindered by limited understanding of the molecular basis of hiPSC-CM development, making it impossible to apply the appropriate cues to optimize stem cell fate and phenotype [5].…”

The Role of Macrophages in the Infarcted Myocardium: Orchestrators of ECM Remodeling

“…The myocardium is a multicellular complex tissue comprised of a range of distinct cell-types. Cardiomyocytes (CMs) constitute approximately one third of resident myocardial cells by number (3), with the remaining two thirds referred to as non-excitable cells (non-CMs), such as fibroblasts, smooth muscle cells, endothelial cells, autonomic motor neurons, and immune cells, such as mast cells and macrophages (4). While CMs possess inherent conduction capabilities which mediate the characteristic contractile forces of the heart, non-CMs are responsible for matrix deposition, vascularization and autonomic regulation (5).…”

Engineered models of the human heart: Directions and challenges

“…It has become increasingly clear that incorporation of other cell types is crucial for proper CM function and therefore complex physiological modeling ( Wang et al., 2018 ). Many 3D models rely on self-assembly of a hydrogel mixed with CMs and fibroblasts ( Breckwoldt et al., 2017 ; Tiburcy et al., 2017 ) or endothelial cells (ECs) ( Giacomelli et al., 2017c ).…”