Capturing Cardiogenesis in Gastruloids

Integrating central and peripheral neurons in elongating multi-lineage-organized gastruloids

“…Gastruloids offer an ability to study the co-development of interconnected systems and organogenesis that is not currently addressable by single-organoid methods. To date, gastruloid studies have primarily applied mouse ESCs to dissect polarized developmental processes with spatiotemporal accuracy 4,[6][7][8][9] . No human stem cell studies outside of this current work on EMLOs have extended early gastruloids to larger, more interconnected states composed of co-developed integrated tissue precursors, or have evaluated the co-integration of CNS and PNS correlates in a multi-lineage study.…”

“…Given the range of cell types and developmental structures observed, it is plausible that EMLOs are formed by two early pools of cellular building blocks having either mesendoderm or neuromesodermal progenitor-like identity, and whose interaction enables myriad downstream integrated tissues, including the gut tube and associated splanchnic mesoderm, that together are known to drive organogenesis 9,12,35 . Cardiac development depends on a multitude of interactions between first and second heart field progenitors and NCCs 9 , and is closely related to the foregut.…”

“…In addition to neuronal pattern coordination, we hypothesize that the gut tube conspires with splanchnic mesoderm in EMLOs to create a microenvironment that is permissive to cardiogenesis (Fig. 6) 9,35 . In one previous hiPSC organoid study 36 , co-emergence of cardiac and intestinal tissue was demonstrated in spheroids, but lacked neural components and did not elongate into compartmentalized bodies or produce robust epithelial tubes or track interaction of networks over time.…”

“…As such, a shift towards new organoid models, deemed gastruloids, that more accurately reflect early development in a multilineage, embryo-like context has emerged 3 . Pioneered using mouse embryonic stem cells (mESCs) 4 , and in one study using human embryonic stem cells (hESCs) for anterior-posterior organization 5 , gastruloids have been applied in vitro to demonstrate symmetry-breaking and axial elongation events 4,6 , somitogenesis 7,8 , and cardiogenesis 9 . Yet, while gastruloids provide a means to interrogate developmental processes with unprecedented detail in vitro, no study using mESCs or human stem cells have investigated the co-emergence of central and peripheral nervous system correlates.…”

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

“…We observed the co-emergence of mesoderm and endoderm cell lineages, resulting in unique multilineage organoids able to spontaneously organize the formation of complex structures similar to the developing heart and gut. Multiple in vitro models have been developed to study various aspects of the heart, including patterning constructs (Ma et al , 2015), gastruloids/organoids (Lee et al , 2020;Rossi et al , 2020),(Drakhlis et al , 2021) (development), and engineered microtissues (homeostasis and maturation) (Ronaldson-Bouchard et al , 2018;Hookway et al , 2019;Mills et al , 2017;Macqueen et al , 2018). However, models that recapitulate heart morphogenic dynamics (i.e.…”