Self-organization of organoids from endoderm-derived cells

Abstract

Organoids constitute biological systems which are used to model organ development, homeostasis, regeneration, and disease in vitro and hold promise for use in therapy. Reflecting in vivo development, organoids form from tissue cells or pluripotent stem cells. Cues provided from the media and individual cells promote self-organization of these uniform starting cells into a structure, with emergent differentiated cells, morphology, and often functionality that resemble the tissue of origin. Therefore, organoids provide a complement to two-dimensional in vitro culture and in vivo animal models of development, providing the experimental control and flexibility of in vitro methods with the three-dimensional context of in vivo models, with fewer ethical restraints than human or animal work. However, using organoids, we are only just beginning to understand on the cellular level how the external conditions and signaling between individual cells promote the emergence of cells and structures. In this review, we focus specifically on organoids derived from endodermal tissues: the starting conditions of the cells, signaling mechanisms, and external media that allow the emergence of higher order self-organization.

Keywords: Emergence; Intestine; Liver; Lungs; Pancreas; Prostate.

Fig. 1

Illustration of endoderm-derived organoids specifying the source of cells, either organ-derived primary cells or PSC-derived cells, that form organoids as well as their representative morphologies. Note that the organoid architecture is not always the same depending of which cell type is used as a source. NA, not applicable means that no organoid of this kind is known to the authors. Representative citations are listed in Table S1

Fig. 2

General overview of methods used for generating endoderm-derived tissue organoids. Methods 1–4 depict the generation of organoids from pluripotent stem cells (PSCs). Method 5 schematizes the prevalent method used for producing organoids from primary tissue-derived cells. Representative citations are listed in Table S1

Fig. 3

YAP-Notch signaling cross talk promotes Paneth cell differentiation and intestinal stem cell niche reestablishment. At the onset of the culture, intestinal stem cells lose the Lgr5 expression and have uniform YAP (blue) nuclear localization. Variability in YAP cellular localization occurs with organoid growth and when a critical cell number is reached, the first Paneth cell emerges and expresses lysozyme (Lyz) and the Notch ligand delta-like 1 (Dll1) which activates the Notch1 (N1) receptor on neighboring cells. These cells lose YAP nuclear localization and re-express Lgr5, making them competent to receive Wnt signals from Paneth cells. Lgr5 re-expressing cells express Hes1: a readout for active Notch signaling, which may contribute to Notch lateral inhibition with the neighboring Paneth cell forming a negative feedback loop to maintain its identity