The Current State of Research into Embryo Models from Stem Cells

Box 1 Definition of Terms • Conceptus: the products of conception at all stages of development from zygote to birth. These include the embryo proper, the fetus, the placenta, and all extraembryonic membranes. The term “embryo proper” refers to those parts of the conceptus that will form the new body and excludes the extraembryonic tissues. Often, the terms “embryo” and “conceptus” are used interchangeably.

• Pre-implantation stages of development: the first few days of development, from fertilization to implantation, during which the conceptus travels down the oviduct toward the uterus. It encompasses the 7–9 days after fertilization in humans.

• Implantation: the process of attachment and invasion of the conceptus to the uterine tissues that occurs around day 7–9 after fertilization in humans. Implantation establishes the fetal-maternal interface leading to later placental development. Implantation is mediated by the polar (embryonic side near the epiblast) and mural trophectoderm cells (abembryonic side opposite the epiblast) of the blastocyst.

• Post-implantation stages of development: the stages of development after the conceptus is embedded in the uterine tissues.

• Gastrulation: the process by which the three germ layers of the embryonic compartment of the conceptus are formed. Gastrulation begins around day 14 in humans.

• Primitive streak: the embryonic structure that establishes bilateral symmetry (alignment of equivalent structures on both sides of the anterior-posterior axis), the site of gastrulation, and the formation of the germ layers. In humans, the primitive streak appears after 14 days.

• Embryonic and fetal stages: the embryonic stage begins with the division of the zygote and encompasses the development of the body plan and formation of the organs. This is followed by the fetal stage, during which growth and maturation of tissues and organs occurs. In humans, the fetal stage begins during the 9th week after fertilization and continues to birth. Beginning with fertilization, the mammalian conceptus (see Box 1 for terminology) goes through a characteristic developmental program with two essential outcomes: (1) the formation of extraembryonic tissues that establish connections with the maternal tissue and fuel the development of the embryo proper and (2) the generation of the three embryonic germ layers of cells that are the building blocks of the future organs. These two processes lay the groundwork for the developing embryo to form a fetus.

Although none of these models has yet been demonstrated to be competent to develop for more than a few days in vitro, we can envision that cell culture methodologies could be refined to a point where the models capture key features of early mammalian development with sufficient fidelity to minimize differences from the conceptus itself. When applied to human cells, such refinements will greatly enhance the power of the models but will also elevate ethical concerns over the conduct of the research.