Stem cell insights into human trophoblast lineage differentiation

Abstract

Human TSC models have the potential to revolutionize our understanding of trophoblast differentiation, allowing us to make significant gains in understanding the underlying pathology of pregnancy disorders and to test potential therapeutic interventions on cell function in vitro. In order to do this, a collaborative effort is required to establish the criteria that define a human TSC to confirm the presence of human TSCs in both primary isolates and to determine how accurately trophoblast-like cells derived from current model systems reflect trophoblast from primary tissue. The in vitro systems currently used to model early trophoblast lineage formation have provided insights into early human placental formation but it is unclear whether these trophoblast-like cells are truly representative of primary human trophoblast. Consequently, continued refinement of current models, and standardization of culture protocols is essential to aid our ability to identify, isolate and propagate 'true' human TSCs from primary tissue.

Derivation of macaque trophoblast stem cells

“…Human ESCs upon treatment with BMP differentiate to trophoblast-like cells 18,19 , however, these cells do not continue to proliferate nor is differentiation tightly controlled. There is also considerable variation in BMP4 treatment protocols leading to differing expression profiles and phenotypes 21,22 . The ESC derived trophoblasts express gene signatures representative of a more primitive trophoblast cell that would be present near the time of implantation 21 , as their gene expression profiles differ from primary villous cytotrophoblasts.…”

“…The ESC derived trophoblasts express gene signatures representative of a more primitive trophoblast cell that would be present near the time of implantation 21 , as their gene expression profiles differ from primary villous cytotrophoblasts. An alternative approach to obtaining trophoblast cell lines has been to isolate primary trophoblasts from early first trimester placental tissue 22 . It is postulated that a TSC niche resides in the early human first trimester placenta 8,[22][23][24] , where these cells are a proliferative, less differentiated progenitor cell population that gives rise to both villous cytotrophoblasts that fuse to form the syncytia as well as extravillous trophoblast (EVT) progenitor cells at the cell column tips 25 .…”

“…Self-renewal of the trophoblast side-population was not demonstrated nor have the cells been characterized in their ability to differentiate to both syncytiotrophoblasts (ST) or EVTs. Altogether, the isolation and characterization of human TSC populations has been limited given the uncertainty of which markers truly define primitive or early trophoblasts and TSCs 22 .…”

Constitutional activation of BMP4 and WNT signalling in hESC results in impaired mesendoderm differentiation

“…Therefore, it cannot be excluded that the subline carries variants in regulatory regions not covered by our sequencing approach. WNT activation is necessary to induce definitive endoderm differentiation, and the most common approach of inducing differentiation towards trophoblast-like cells is BMP4 treatment (reviewed in Gamage et al, 2016). Therefore, we aimed at validating the implication of these pathways in the misspecification observed in VUB03_S2.…”

Establishment of macaque trophoblast stem cell lines derived from cynomolgus monkey blastocysts

“…Trans-differentiation of human ESC to trophoblast-like cells by BMP4 treatment has also been adopted 2 . However, the adequacy of trans-differentiation system remains somewhat controversial, since the gene expression profile of the resulting trophoblast-like cells do not resemble that of primary trophoblast cells, moreover they express other cell lineage markers 2,10 . Recently, the trans-differentiation protocol from human ESC to trophoblast-like cells was improved in so-called BAP treatment 11 .…”