Heart organoids and tissue models for modeling development and disease

Abstract

Organoids, or miniaturized organs formed in vitro, hold potential to revolutionize how researchers approach and answer fundamental biological and pathological questions. In the context of cardiac biology, development of a bona fide cardiac organoid enables study of heart development, function, and pathogenesis in a dish, providing insight into the nature of congenital heart disease and offering the opportunity for high-throughput probing of adult heart disease and drug discovery. Recently, multiple groups have reported novel methods for generating in vitro models of the heart; however, there are substantial conceptual and methodological differences. In this review we will evaluate recent cardiac organoid studies through the lens of the core principles of organoid technology: patterned self-organization of multiple cell types resembling the in vivo organ. Based on this, we will classify systems into the following related types of tissues: developmental cardiac organoids, chamber cardiac organoids, microtissues, and engineered heart tissues. Furthermore, we highlight the interventions which allow for organoid formation, such as modulation of highly conserved cardiogenic signaling pathways mediated by developmental morphogens. We expect that consolidation and categorization of existing organoid models will help eliminate confusion in the field and facilitate progress towards creation of an ideal cardiac organoid.

Keywords: Cardiac organoid; Engineered heart tissue; Gastruloid; Self-organization.

Figure 1:

Staging in vitro models of the heart to in vivo heart development. A. Embryo undergoing gastrulation. Precardiac organoid models attempt to recapitulate this stage of development. B.-C. Cardiac crescent formation and merging to form the linear heart tube. Developmental cardiac organoids model this stage of development. D. Embryo undergoing rightward looping and chamber formation. Chamber cardiac organoids recapitulate this stage of development and microtissues offer insight into the cell type-cell type interactions between cardiomyocytes and stromal cells. E. Maturation of cardiomyocytes to promote adult heart function. Engineered heart tissues attempt to promote a more adult and in vivo-like state of cardiac tissues.

Figure 2:

Summary of noteworthy models of in vitro models of the heart. Developmental cardiac organoids [103] form vascular networks, cardiac crescent-like, and linear heart tube-like structures with the addition of pro-cardiogenic factors bFgf, Vegf, and ascorbic acid. Chamber cardiac organoids [106] form patterned chambers regulated by a Wnt-Bmp signaling axis. Microtissues are aggregates of CMs and stromal cell types which allow for study of cell type-cell type interactions. Engineered heart tissues are models of a piece of the heart, and enable enhanced CM maturation for drug discovery and disease modeling.