Trophoblast stem cells

Abstract

Trophoblast stem cells (TSC) are the precursors of the differentiated cells of the placenta. In the mouse, TSC can be derived from outgrowths of either blastocyst polar trophectoderm (TE) or extraembryonic ectoderm (ExE), which originates from polar TE after implantation. The mouse TSC niche appears to be located within the ExE adjacent to the epiblast, on which it depends for essential growth factors, but whether this cellular architecture is the same in other species remains to be determined. Mouse TSC self-renewal can be sustained by culture on mitotically inactivated feeder cells, which provide one or more factors related to the NODAL pathway, and a medium supplemented with FGF4, heparin, and fetal bovine serum. Repression of the gene network that maintains pluripotency and emergence of the transcription factor pathways that specify a trophoblast (TR) fate enables TSC derivation in vitro and placental formation in vivo. Disrupting the pluripotent network of embryonic stem cells (ESC) causes them to default to a TR ground state. Pluripotent cells that have acquired sublethal chromosomal alterations may be sequestered into TR for similar reasons. The transition from ESC to TSC, which appears to be unidirectional, reveals important aspects of initial fate decisions in mice. TSC have yet to be derived from domestic species in which remarkable TR growth precedes embryogenesis. Recent derivation of TSC from blastocysts of the rhesus monkey suggests that isolation of the human equivalents may be possible and will reveal the extent to which mechanisms uncovered by using animal models are true in our own species.

FIG. 1.

Diagram to illustrate the origin and fate of TSC in the mouse. Stem cell precursors in polar TE are hypothesized to give rise to a population of TSC. TSC are located adjacent to the developing epiblast, which arises from the ICM (see Fig. 2). The TSC self-renew but also generate faster-dividing, multipotent progenitors that provide the precursors of the differentiated cell types of the placenta. The information shown is speculative, and the differentiated tissue lineages are minimized for simplicity.

FIG. 2.

Diagram to illustrate the dependence of the polar TE in the Day 3.5 blastocyst (A) and TSC in a conceptus at Day 6.5 (B) on factors produced by the ICM and epiblast, respectively, of the mouse conceptus. For simplicity, the polar TE, because of its transient nature, is regarded as the precursor of the “true” TSC population in its initial niche adjacent to the epiblast. FGF4 and NODAL are assumed to be produced by the ICM and epiblast. The insets in A and B show the regions illustrated in the main figures. The diagrams are based on those of Tanaka et al. [16] with permission from AAAS.

FIG. 3.

Development of TR of ungulate species from mural trophectoderm. A) Pig conceptus at about Day 13 of pregnancy, at which stage each can achieve a length of 1 m or greater. The position of the relatively undeveloped embryonic disc is arrowed. B) The formation of the embryonic plate in the goat conceptus, illustrating the loss of polar TE during the early stages of conceptus elongation and the growth of mural TE and underlying extraembryonic endoderm. The expanded blastocyst (B1) is at around Day 10 of pregnancy, but within a few days polar trophectoderm disappears (B2), and the embryonic plate is formed (B3). The location of the TSC “niche,” if it exists in such conceptuses, is unknown. The diagrams are redrawn (with permission) from John R. Fuller's illustrations in Austin [149].