Human trophoblast stem cells: Real or not real?

Abstract

Abnormal trophoblast differentiation is the root cause of many placenta-based pregnancy complications, including preeclampsia and fetal growth restriction. Human trophoblast differentiation is difficult to study due to the lack of a stem cell model. Such a multipotent "trophoblast stem" (TS) cell, with the ability to differentiate into all trophoblast subtypes, has been derived from mouse blastocysts, but attempts to derive similar human cells have failed. We consider here several possibilities for the TS cell niche in the human placenta. Aside from discussion of such a niche in the pre-implantation blastocyst, we discuss evidence for these TS cells residing in the post-implantation villous cytotrophoblast layer, or even in the non-trophoblast portions, of the human placenta. It is our hope that recognition of the niche would lead to successful derivation and in vitro establishment of such cells, which could then be disseminated widely to the placental biology community for advancing the field. Availability of self-renewing human TS cells, whose gene expression and environment could be manipulated, will provide a platform, not just for the study of pathophysiology of placental disease, but also for the discovery of diagnostic biomarkers and therapeutic targets for common pregnancy complications.

Keywords: Blastocyst; Placenta; Progenitor cells; Trophoblast; Trophoblast stem cells.

Figure 1

Schematic diagram demonstrating potential trophoblast stem cell niches in the human placenta at various gestational stages. (A) In the preimplantation stage, embryonic stem cells (hESC) lines have been derived from early blastocysts, which appear to show totipotency (the ability to differentiate into endoderm, mesoderm, ectoderm, and trophectoderm, the latter defined as CDX2⁺ cells). In the blastocyst-proper, two different cell lineages are observed: trophectoderm (TE) and inner cells mass (ICM). Unlike mouse TE, in the human blastocyst, CDX2 expression initially overlaps with OCT4 in TE, where GATA3 is also expressed. (B) In the post-implantation placenta, potential trophoblast progenitor cell populations include cytotrophoblast subpopulations, such as those which co-express p63, CDX2, and ELF5, as well as ITGA4⁺ cells in the chorionic mesenchyme. Proximal cell column trophoblast are proliferative, but deemed as committed precursors to the invasive extravillous trophoblast lineage. TBPC, trophoblast progenitor cell; CTB, cytotrophoblast; STB, syncytiotrophoblast; EVT extravillous cytotrophoblast; MC, mesenchymal cell; FV, fetal vessel.