Blastocyst-like structures generated solely from stem cells

Abstract

The blastocyst (the early mammalian embryo) forms all embryonic and extra-embryonic tissues, including the placenta. It consists of a spherical thin-walled layer, known as the trophectoderm, that surrounds a fluid-filled cavity sheltering the embryonic cells . From mouse blastocysts, it is possible to derive both trophoblast and embryonic stem-cell lines , which are in vitro analogues of the trophectoderm and embryonic compartments, respectively. Here we report that trophoblast and embryonic stem cells cooperate in vitro to form structures that morphologically and transcriptionally resemble embryonic day 3.5 blastocysts, termed blastoids. Like blastocysts, blastoids form from inductive signals that originate from the inner embryonic cells and drive the development of the outer trophectoderm. The nature and function of these signals have been largely unexplored. Genetically and physically uncoupling the embryonic and trophectoderm compartments, along with single-cell transcriptomics, reveals the extensive inventory of embryonic inductions. We specifically show that the embryonic cells maintain trophoblast proliferation and self-renewal, while fine-tuning trophoblast epithelial morphogenesis in part via a BMP4/Nodal-KLF6 axis. Although blastoids do not support the development of bona fide embryos, we demonstrate that embryonic inductions are crucial to form a trophectoderm state that robustly implants and triggers decidualization in utero. Thus, at this stage, the nascent embryo fuels trophectoderm development and implantation.

Bioengineered microenvironment to culture early embryos

“…The formation of embryoid bodies can be divided into four stages: blastocyst, early post‐implantation, gastrulation and post‐gastrulation. Blastocyst formation reveals that ES maintains TS proliferation and self‐renewal during embryogenesis and regulates trophoblast epithelial morphogenesis through BMP4/Nodal‐KLF6 . Early post‐implantation illustrates the role of Nodal signalling during ETS‐embryogenesis .…”

The underdeveloped innate immunity in embryonic stem cells: The molecular basis and biological perspectives from early embryogenesis

“…It is exciting that recent advances in three-dimensional organoid culture techniques have led to the generation of primitive "organs" from ESC-differentiated cells. 129,130 This model could be extended to investigate innate immunity development at the blastocyst stage. 129,130 This model could be extended to investigate innate immunity development at the blastocyst stage.…”

“…128 It is now feasible to reconstitute a blastocyst-like structure with ESCs and TSC-derived trophoblasts that can recapitulate certain developmental events of early embryogenesis. 129,130 This model could be extended to investigate innate immunity development at the blastocyst stage. With the knowledge and resources that have been obtained from stem cell research, the emergence of new tissue culture models and molecular tools, such as gene editing, will provide more exciting interdisciplinary opportunities for a deeper understanding of early embryogenesis, immunology, and reproductive biology, which is otherwise difficult or impossible with in vivo studies.…”

Direct synthesis of self-organized blastocyst-like cysts derived from human pluripotent stem cells

“…Recent studies have reported methods to generate blastocyst-like structures for experimental mouse models 3,4 . However, these studies used and digested blastocysts from fertilized eggs to obtain embryonic stem cells (ESCs) 5 and trophoblast stem cells (TSCs).…”