A Combined Human Gastruloid Model of Cardiogenesis and Neurogenesis

Abstract

Multi-lineage development from gastruloids is enabling unprecedented opportunities to model and study human embryonic processes and is expected to accelerate ex vivo strategies in organ development. Reproducing human cardiogenesis with neurogenesis in a multi-lineage context remains challenging, requiring spatiotemporal input of paracrine and mechanical cues. Here we extend elongating multi-lineage organized (EMLO) gastruloids to include cardiogenesis (EMLOC) and describe interconnected neuro-cardiac lineages in a single gastruloid model. Contractile EMLOCs recapitulate numerous interlinked developmental features including heart tube formation and specialization, cardiomyocyte differentiation and remodeling phases, epicardium, ventricular wall morphogenesis, chamber-like structures and formation of a putative outflow tract. The EMLOC cardiac region, which originates anterior to gut tube primordium, is progressively populated by neurons in a spatial pattern mirroring the known distribution of neurons in the innervated human heart. This human EMLOC model represents the first multi-lineage advancement for the study of coincident neurogenesis and cardiogenesis.

Biotechnological advances and applications of human pluripotent stem cell-derived heart models

“…Many groups are recapitulating aspects of embryogenesis of organs ex vivo in hPSC organoid and gastruloid technologies ( Simunovic and Brivanlou, 2017 ). This includes early gastruloid models with regions expressing cardiogenic and heart field markers ( Rossi et al, 2020 ) as well as complex multi-chambered and innervated human hearts ( Olmsted and Paluh, 2022 ). Schultheiss et al (1997) revealed that bone morphogenic protein 4 (BMP4) was required for myocardial differentiation during early embryonic development in ESCs.…”

“…Wnt activation is also applied in the elongating multilineage organized cardiac (EMLOC) advanced heart gastruloid. All-in-all, the current novel state of cardiac organ gastruloids in mice ( Rossi et al, 2020 ) and humans ( Olmsted and Paluh, 2022 ) are largely focused on heart development and congenital heart defects and cardiotoxicity screening of drugs has not yet been explored.…”