Developmental co-emergence of cardiac and gut tissues modeled by human iPSC-derived organoids

Abstract

During embryogenesis, organs in close proximity exhibit paracrine signaling that contributes to the development and fate of each tissue. Organoids are in vitro models that mimic tissue formation and heterogeneity, but lack the paracrine input of surrounding organs. Here, we describe a human multilineage iPSC-derived organoid that recapitulates cooperative cardiac and gut development, and exhibits greater morphological complexity than any single-lineage organoids described so far. In contrast with previous cardiac models devoid of endoderm (gut/intestine tissue), this organoid exhibited a heart wall-like structure, cardiomyocyte compartmentalization, enrichment of atrial/nodal cells, and functional maturation. Overall, this study demonstrates the ability to generate distinct functional tissues originating from different germ lineages within a single organoid model, an advance that will further the examination of multi-tissue interactions during development and disease. One Sentence Summary:Cooperative emergence of heart and intestine in an organoid recapitulates development and improves tissue-specific maturation.

Bi-directional Impacts of Heterotypic Interactions in Engineered 3D Human Cardiac Microtissues Revealed by Single-Cell RNA-Sequencing and Functional Analysis

“…Circular regions of interest (ROI; 75-pixel diameter) were selected at the center of each microtissue and the mean fluorescent intensity values were plotted against time. Metrics of calcium transient kinetics, such as amplitude, stroke velocities, and beat rate, were analyzed using a custom python script 68 . Source code is available at https://github.com/david-a-joy/multilineage-organoid.…”

Cardioids reveal self-organizing principles of human cardiogenesis

“…These have proven immensely useful to measure contraction force, perform compound screens and model structural muscle and arrhythmogenic disorders. Similarly, mouse and human PSC-derived 3D cardiac models including spherical aggregates (microtissues) of CMs and other cardiac cell types (Giacomelli et al, 2017;Richards et al, 2020), have been reported as promising tools for drug discovery; and embryoid models (Rossi et al, 2019;Silva et al, 2020) as providing insights into germ layer interactions in early organogenesis. However, existing models do not recapitulate cardiac-specific self-organizing patterning and morphogenesis to acquire in vivo-like architecture, and they are therefore limited as models of early human cardiogenesis and congenital heart disease.…”

Translating Embryogenesis to Generate Organoids: Novel Approaches to Personalized Medicine

“…This is partly due to the complex architecture of the heart requiring multilineage interactions and paracrine signaling from adjacent tissues. A recent study utilized co-emerging cardiac-like mesoderm and gut-like endoderm from iPSCs that can attain adult heart-type complexity with non-contractile myocytes and blood vessels surrounding it ( Silva et al, 2020 ). Human PSCs can intrinsically self-organize to form cardiac mesoderm without exogenous extracellular matrix proteins and consist of separate myocardial and endothelial layers.…”

“…Multi-lineage organoids generated from co-emerging cardiac and gut lineage specification from iPSCs can be useful to model heart complexity better than conventional cardiac organoids. These organoids consist of mature cardiomyocytes, stromal epicardial cells, and blood-vessel-like structures along with the primitive gut that resembles the intestine ( Silva et al, 2020 ). The emergence of multilineage organ models will be useful to map paracrine interaction and also understand the role of adjacent organ tissues required for organ maturation.…”