Congenital heart disease (CHD) is the major cause for prenatal mortality. CHD can be originated by genetic mutations, environmental factors or both, however for the majority of diagnosed cases the underlying origin is unknown. CHDs onset occurs early in development and can selectively affect specific regions of the embryonic heart. Characterization of disease aetiology is particularly challenging, as the human embryonic heart is inaccessible. In particular, there are no human in vivo references for some molecular and electrophysiological landmarks at early stages of cardiogenesis, between 19 and 28 days post fertilization.
Most of our understanding on human CHD aetiology comes from studies on animal models, which present obvious limitations including different developmental speed compared to human embryos, inaccessibility and species-specific differences. To overcome these limitations, in vitro models have recently been developed, including hiPSC-derived self-organizing cardioids. Cardioids can mimic aspects of development as they can specify, pattern and shape into chamber-like structures. However, in vivo, cardiac chambers co-develop smoothly and a multi-chamber organoid model to study early stages cardiac morphogenesis was still missing. The paper by Schmidt et al describes the establishment of a multi-chamber human cardioid platform. They use this system to unravel how interacting cardiac regions coordinate their contraction and function, as well as investigating the impact of mutations, drugs and environmental factors on specific regions of the developing human heart.
The authors first generated progenitors subsets with distinct identities of the first, anterior and superior heart field, and then generated cardioids with compartment specific (including atria, L/R ventricle, and AVC and OFT regions) in vivo-like gene expression profiles, morphologies and function. Physical aggregation of different cardioids subtypes at specific time points resulted in structural and electrochemical connection and coordinated contraction. This allowed the study of the functional interactions between compartments, including Ca2+ signal propagation, action potential characterization and directionality of electric signal propagation. Generation of multi-chamber cardioids from hiPSCs knockout for ISL1, TBX5 and FOXF1 genes recapitulated several findings of the corresponding animal models, thus showing that the cardioid platform can be employed to dissect stage and compartment-specific human genetic defects of cardiac specification, morphogenesis and function. Finally, the authors tested the effects of several teratogens and drugs on the cardioid system, showing that is extremely sensitive to different compounds, in a drug and compartment-specific way.
A significant advantage and novelty of this work is the deep and comprehensive phenotyping used to explore multiple aspects of the early stages of cardiogenesis, including ontology of contraction, signal propagation, differentiation speed, specification direction and efficiency, and morphogenesis. This is particularly relevant to analyse cases of embryonic cardiac failure that have been attributed to faulty specification and morphogenesis, but where defects in early contraction and in signal propagation between cardiac chambers might have been the underlying cause.
In conclusion, this work has broad implications for studying the effects of mutations and drugs on human cardiac biology in a human multi-compartment cardiac platform and to correlate them to cardiac defects observed in patients. These results cannot substitute for the mouse embryo model, but represent a powerful complement to it.
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