BMP4 regulation of human trophoblast development

Abstract

Since the derivation of human embryonic stem cells, and the subsequent generation of induced pluripotent stem cells, there has been much excitement about the ability to model and evaluate human organ development in vitro. The finding that these cells, when treated with BMP4, are able to generate the extraembryonic cell type, trophoblast, which is the predominant functional epithelium in the placenta, has not been widely accepted. This review evaluates this model, providing comparison to early known events during placentation in both human and mouse and addresses specific challenges. Keeping in mind the ultimate goal of understanding human placental development and pregnancy disorders, our aim here is two-fold: to distinguish gaps in our knowledge arising from mis- or over-interpretation of data, and to recognize the limitations of both mouse and human models, but to work within those limitations towards the ultimate goal.

Fig. 1

H&E staining of early placenta tissue, from a rare archived 16-day human blastocyst specimen. (A) Continuous STB layer covering underlying CTB layer. (B) Column CTB and a few multinucleated “giant cells.” Some EVT also exist in chorionic (fetal) membranes (C) and intraplacental trophoblastic islands (D).

Fig. 2

Immunohistochemistry staining for CDX2 in early (7-week) placental tissue. CDX2 (brown) is expressed only in a subset of CTBs. The tissue section is counterstained with hematoxylin (blue).

Fig. 3

Proposed model of BMP4-directed trophoblast differentiation of hPSCs. Self-renewing hPSCs are maintained under feeder-free conditions with bFGF. For trophectoderm differentiation, hPSCs are cultured in feeder-conditioned medium supplemented with 10 ng/ml BMP4 for up to 8 days. BMP4-treated hPSCs undergo a p63/KRT7/CDX2 triple-positive CTB “stem cell” state prior to terminal differentiation into HLA-G/H-hCG positive EVT and hCG/KLF4 positive STB.