Abstract
Our understanding of the spatiotemporal regulation of cardiogenesis is hindered by the difficulties in modeling this complex organ currently by in vitro models. Here we develop a method to generate heart organoids from mouse embryonic stem cell-derived embryoid bodies. Consecutive morphological changes proceed in a self-organizing manner in the presence of the laminin-entactin (LN/ET) complex and fibroblast growth factor 4 (FGF4), and the resulting in vitro heart organoid possesses atrium- and ventricle-like parts containing cardiac muscle, conducting tissues, smooth muscle and endothelial cells that exhibited myocardial contraction and action potentials. The heart organoids exhibit ultrastructural, histochemical and gene expression characteristics of considerable similarity to those of developmental hearts in vivo. Our results demonstrate that this method not only provides a biomimetic model of the developing heart-like structure with simplified differentiation protocol, but also represents a promising research tool with a broad range of applications, including drug testing.
Highlights
Our understanding of the spatiotemporal regulation of cardiogenesis is hindered by the difficulties in modeling this complex organ currently by in vitro models
In vivo cardiogenesis occurs via consecutive morphological changes that include cardiac crescent formation on embryonic day 7.5 (E7.5), the beating heart tube derived from endothelial cells (ECs) and CMs (E8), the looping heart tube on E9.5 (with a beating force or outflow tract (OFT)) and formation of a four-chambered heart[1,2,3,4,5], exhibiting regionality starts around E10.5 and maturation becomes completed at E14.5 (Supplementary Fig. 1a)
We first thought to determine the minimal set of growth factors needed to promote cardiogenic differentiation in vitro and hypothesized fibroblast growth factor 4 (FGF4) is important for a necessary condition for in vitro reconstruction of cardiogenesis, given that FGF and FGFR1 are required for heart development
Summary
Our understanding of the spatiotemporal regulation of cardiogenesis is hindered by the difficulties in modeling this complex organ currently by in vitro models. Consecutive morphological changes proceed in a self-organizing manner in the presence of the laminin-entactin (LN/ET) complex and fibroblast growth factor 4 (FGF4), and the resulting in vitro heart organoid possesses atrium- and ventricle-like parts containing cardiac muscle, conducting tissues, smooth muscle and endothelial cells that exhibited myocardial contraction and action potentials. We report the generation of a heart organoid with atrium- and ventricle-like structures showing the ultrastructural, histochemical and gene expression profile similarities to embryonic hearts in the presence of the laminin-entactin (LN/ ET) complex[22] in the ECM and exogenous fibroblast growth factor 4 (FGF4)[20] via consecutive morphological changes like selforganization and, without the requirement of complex differentiation protocols
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