Synthetic embryology: Early mammalian embryo modeling systems from cell cultures

Abstract

Recently, the fields of embryology, developmental biology, stem cell biology, and cell reprogramming, have intersected with synthetic embryo systems (SESs) from cultured cells. Among such SESs, several approaches have engaged early-embryo-like cells, cells with atypical potency, or assembled traditional in vitro stem cell populations with synergy, to advance life discovery systems that may yield emergent knowledge and biotechnical advance. Such models center on the competent generation of blastocyst-like and post-implantation embryo-like forms. Our group, and several others have recently pioneered unique SES strategies covering a broad spectrum of key early embryo-like developmental stages and features to seed an emerging SES field. Herein, we provide a comprehensive perspective of synthetic embryology and the powerful promise that excites us.

Reprogramming epiblast stem cells into pre-implantation blastocyst cell-like cells

“…Throughout this study we observed traces of gene expression suggesting that iPE and PE-like region cells shared a pluripotent-like origin with the iEPI population, reminiscent of the GATA4 + , GATA6 + , and PDGFRA + cells arising at the inner face of BCLH pluripotent cells ( Kime et al., 2019 ). Consideration for PE cells has weighed heavily on various SESs ( Tomoda and Kime, 2021 ), and we suspect that correct hypoblast formation will remain a hinge point for healthy embryoid development.…”

“…Early embryos were used to derive various pluripotent and multipotent stem cell lines with characteristics and chimera-integrating potential analogous to the assumed embryonic origin ( Evans and Kaufman, 1981 ; Martin, 1981 ). However, the ability to form synthetic embryos from cultured cells had been elusive until recent advances enabled in vitro synthetic embryo systems (SESs) ( Tomoda and Kime, 2021 ).…”

“…SESs are part of a newly emerging generation of models akin to organoids, but reflecting early embryology through “embryoids” that are far more convincing ( Harrison et al., 2017 ; Kime et al, 2018 , 2019 ; Rivron et al., 2018 ; Shahbazi and Zernicka-Goetz, 2018 ; Tomoda and Kime, 2021 ; Zheng et al., 2019 ). Several SESs exist, and some focus on modeling the blastocyst (BC) and its three layers: trophectoderm (TE), primitive endoderm (PE), and pluripotent pre-implantation epiblast (EPI).…”

“…Other SESs, including those produced by our group, involve cell reprogramming or unique cell plasticity states that give rise to BC-like cysts from single cultures. Various approaches building on BC-like cyst formation in vitro continue to be developed and explored as each SES uniquely broadens embryology ( Tomoda and Kime, 2021 ).…”

Synthetic living machines: A new window on life

“…Can cellular collectives cooperate to form novel target morphologies in the absence of genetic change? The study of artificial embryogenesis ( Metzger et al., 2018 ; Ouyang and Chen, 2010 ; Rosado-Olivieri and Brivanlou, 2021 ; Shao and Fu, 2020 ; Tomoda and Kime, 2021 ) provides a large option space of novel model systems where the relationship between evolutionary forces, genomic information, and structural/behavioral outcomes can be studied. Examples include two recent types of novel living constructs called “Xenobots” (a portmanteau word joining “biobot” and “Xenopus,” as the cells were sourced from embryos of the frog Xenopus laevis ) ( Kriegman et al., 2020 ) ( Figure 4 D-4I).…”