Organoids and the genetically encoded self‐assembly of embryonic stem cells

Abstract

Understanding the mechanisms of early embryonic patterning and the timely allocation of specific cells to embryonic regions and fates as well as their development into tissues and organs, is a fundamental problem in Developmental Biology. The classical explanation for this process had been built around the notion of positional information. Accordingly the programmed appearance of sources of Morphogens at localized positions within a field of cells directs their differentiation. Recently, the development of organs and tissues from unpatterned and initially identical stem cells (adult and embryonic) has challenged the need for positional information and even the integrity of the embryo, for pattern formation. Here we review the emerging area of organoid biology from the perspective of Developmental Biology. We argue that the events underlying the development of these systems are not purely linked to “self‐organization,” as often suggested, but rather to a process of genetically encoded self‐assembly where genetic programs encode and control the emergence of biological structures.

Embryoids, organoids and gastruloids: new approaches to understanding embryogenesis

“…However, what these mechanisms are is still a mystery. The timing of formation of some organoids, such as brain organoids, more or less follows developmental timing in vivo, depending on the assay used (Gaspard et al, 2008;Turner et al, 2016). Furthermore, the timing of neural differentiation seems to be species-specific, as seen in vivo, as illustrated by the slower neural maturation of hESCs compared with primate ESCs (Otani et al, 2016) and by the faster in vitro differentiation of mouse cells into neurons compared with human cells (Wichterle et al, 2002).…”

“…In general, an organoid is defined as a structure in which pluripotent or progenitor stem cells are differentiated into multiple cell populations that self-organize/assemble into a tissue that resembles an organ in vivo (Clevers, 2016;Fatehullah et al, 2016;Kicheva and Briscoe, 2015;Lancaster and Knoblich, 2014;Sasai et al, 2012;Turner et al, 2016). In a similar vein, researchers have also generated structures referred to as embryoid bodies, embryoids and gastruloids (see Glossary, Box 1; Fig.…”

“…We consider the term embryoid to represent a more organized embryoid body that arises as a consequence, for instance, of cell polarization induced by the ECM in the surrounding medium or due to the correct topology of multiple cell types representing an embryo at a certain time of development. Gastruloids, by contrast, are models of a gastrulating embryo, either in 2D (Etoc et al, 2016;Warmflash et al, 2014) or in 3D (Turner et al, 2016;van den Brink et al, 2014). Self-assembly/ organization has also been observed directly in attached mammalian blastocysts in vitro.…”

“…We will not focus on detailed molecular aspects of signaling and patterning nor on methods to produce organoids, as these topics have been thoroughly reviewed elsewhere (e.g. Clevers, 2016;Fatehullah et al, 2016;Kicheva and Briscoe, 2015;Lancaster and Knoblich, 2014;McCauley and Wells, 2017;Turner et al, 2016). Instead, we focus on the three ingredients that we believe are key for creating a functional organoid: (1) self-organization/assembly, which involves the correct positioning of cells with respect to one another; (2) breaking of symmetry, whereby, for instance, a seemingly homogenous cluster of cells gives rise to the body axis; and (3) the control of developmental timing and size.…”

The physics of organoids: a biophysical approach to understanding organogenesis

“…This non-linearity owes to the fact that many governing mechanisms, such as growth, cell type and cell state, are coupled and therefore one cannot completely isolate their effects on the system. As with many biological systems, organoids are deterministic in the sense that the cells follow a given set of rules that rely on cues from their history, such as expressed genes and proteins and specific chromatin modifications (Turner et al, 2016), as well as from their local environment, such as the presence of other cells and the medium in which they are cultured. Note, however, that to reach this deterministic outcome cells often use cues from random …”