Intestinal and optic-cup organoids as tools for unveiling mechanics of self-organizing morphogenesis

Abstract

Organoid, an organ-like tissue reproduced in a dish, has specialized, functional structures in three-dimensional (3D) space. Organoid development replicates the self-organizing process of each tissue development during embryogenesis but does not necessarily require external tissues, illustrating the autonomy of multicellular systems. Herein, we review the developmental processes of epithelial organoids, namely, the intestine, and optic-cup, with a focus on their mechanical aspects. Recent organoid studies have advanced our understanding of the mechanisms of 3D tissue deformation, including appropriate modes of deformation and factors controlling them. In addition, the autonomous nature of organoid development has also allowed us to access the stepwise mechanisms of deformation as organoids proceed through distinct stages of development. Altogether, we discuss the potential of organoids in unveiling the autonomy of multicellular self-organization from a mechanical point of view. This review article is an extended version of the Japanese article, Mechanics in Self-organizing Organoid Morphogenesis, published in SEIBUTSU BUTSURI Vol. 60, p.31-36 (2020).

Keywords: cell autonomy; development; intestinal organoid; optic-cup organoid; tissue mechanics.

Figure 1

Generation of intestinal organoid and its morphogenesis in 3D culture. A section of in vivo mouse intestine (A), where the apical surface is facing the lumen (light blue), and the basal surface is facing the mesenchyme (orange). 3D culture of an isolated crypt (B) generates an intestinal organoid with a 3D structure containing a lumen-enclosed epithelium (C). During development, the organoid initially attains a bulged state (D), and later, transforms into a budded state (E). In this process, lumen volume is reduced, and the crypt bud is protruded. The intestinal organoid as shown here houses different cells such as the stem cells (blue), Paneth cells (pink), and enterocytes (yellow).

Figure 2

Generation of optic-cup organoid and its morphogenesis in 3D culture. In the SFEBq method, A) initially, the dissociated embryonic stem cells (ESC) are harnessed in a tube. B) The cells autonomously form an aggregate, and C) the aggregate forms a lumen-enclosed neuroepithelium. D) In the optic-cup formation, a part of the neuroepithelium protrudes outward to form a semispherical optic vesicle (OV). The OV exhibits further development (i-iv). The inner and outer surfaces of the OV are apical and basal surfaces, respectively (i). The distal part of the OV differentiates into the neural retina (NR) and the surrounding retinal pigment epithelium (RPE) (ii). Upon differentiation, the NR invaginates in the apically convex manner (iii) by gradually increasing the NR curvature. Later, the tissue attains a two-walled cup-like structure with a hinge-shaped NR-RPE boundary (iv).

Figure 3

Modes of actomyosin-dependent epithelial bending. A) Apically concave invagination by apical constriction. Increase in apical actomyosin contractility constricts the apical cell surface, causing the epithelium to bend in an apically concave manner. B) Apically convex invagination by apical relaxation or expansion. Reduction in apical actomyosin contractility or other machineries expands the apical surface, causing the epithelium to bend in an apically convex manner. C) Curvature amplification by lateral constriction. When lateral constriction occurs in an apically or basally curved epithelium, it constricts the thickness of epithelium, amplifying its curvature.

Figure 4

Bending rigidity regulated by epithelial thickness. A) Thicker epithelium has higher bending rigidity, requiring larger external force to bend the epithelium. B) Thinner epithelium has lower bending rigidity, requiring smaller external force to bend the epithelium.

Figure 5

Epithelial deformation regulated by lumen volume. The decrease in lumen volume allows the epithelium to deform freely (A to B), whereas the increase in lumen volume expands the epithelium and prevents its deformation as a constraint (B to A).

Figure 6

Mechanical feedback from the entire tissue to individual cells. A) In the optic-cup formation, the NR invaginates and the NR-RPE boundary is wedged simultaneously. The NR invagination is autonomously caused to generate a bending moment. B) The bending moment generated in the NR is exerted on the NR-RPE boundary, causing a strain at the basal surface. C) The basal strain triggers lateral constriction at the NR-RPE boundary, constricting the epithelial thickness and facilitating the NR invagination.