Speaker: Mana Parast, director of the Perinatal Pathology Service and co-director of the Center for Perinatal Discovery at University of California, San Diego
Title: "Trophoblast stem cells and differentiated progeny in placental development and disease"
Abstract: The human placenta is a poorly-understood transient organ whose proper development and function are critical during pregnancy. Important to the function of this organ are three groups of epithelial cells: cytotrophoblast (CTB) progenitor cells, which either fuse to form syncytiotrophoblast (STB) or undergo an epithelial-to-mesenchymal transition to become invasive extravillous trophoblast (EVT). While mice have been used extensively to understand placental development, application of these studies to the human organ has been limited due to species-specific differences, particularly with regard to trophoblast lineage specification and early differentiation. Recently, several groups have established protocols for derivation of human trophoblast stem cells (hTSC) or self-renewing trophoblast organoids, which can be manipulated to study human trophoblast proliferation and differentiation. However, since these cells can only be derived from early gestation material, their disease potential remains unknown. Over the past 5 years, our lab has developed a protocol for step-wise differentiation of human pluripotent stem cells (hPSC’s, both embryonic stem cells/hESC’s and induced pluripotent stem cells/iPSC’s), first into CTB progenitor cell-like, and subsequently into STB- or EVT-like cells. We have recently shown that, by applying hTSC media to hPSC-derived CTB, we can establish self-renewing TSC-like cells from all our hESC and iPSC lines. Similar to primary hTSC, these cells have the capacity to differentiate into distinct subpopulations of hCG+ multinucleated STB-like, or invasive HLA-G+ EVT-like cells. We have found that downregulation of VGLL1 and TP63, two genes specifically expressed in human trophectoderm and CTB, interferes with trophoblast differentiation of hPSC’s. Most recently, we have established iPSC’s, by reprogramming umbilical cord mesenchymal stem cells from placentas of both normal pregnancies and those complicated by severe early-onset preeclampsia (PE). We have found that PE-iPSC appropriately differentiate into CTB, but in the second step of differentiation, show a significant reduction in proportion of HLA-G+ EVT with little-to-no invasive potential. These data confirm that iPSC’s can recapitulate human trophoblast differentiation associated with both normal and complicated pregnancies.
Host: Geetu Tuteja, associate professor in genetics, development and cell biology at Iowa State University