PTHrP promotes murine secondary trophoblast giant cell differentiation through induction of endocycle, upregulation of giant-cell-promoting transcription factors and suppression of other trophoblast cell types.
The murine trophoblast cell lineage represents an intriguing experimental cell model as it is composed of four trophoblast stem (TS)-derived cell types: trophoblast giant cells (TGCs), spongiotrophoblast, syncytotrophoblast, and glycogen trophoblast cells. To investigate the role of parathyroid hormone-related protein (PTHrP) in TGC differentiation, we analyzed the effect of exogenous PTHrP on secondary TGCs of day 8.5 p.c. ectoplacental cone explant culture. Secondary TGCs expressed PTHrP and PTHR1 receptor in vivo and in vitro. TGCs treated with PTHrP had reduced proliferation and decreased apoptosis starting from day 2 in culture, and enhanced properties of giant cell differentiation: increased DNA synthesis, number of cells with giant nuclei and expression of placental lactogen-II (PL-II). The induction of TGC formation by PTHrP correlated with downregulation of cyclin B1 and mSNA expression, but upregulation of cyclin D1, thus allowing mitotic-endocycle transition. Moreover, PTHrP treatment influenced TGC differentiation by inducing the expression of transcription factors known to stimulate giant cell formation: Stra13 and AP-2gamma, and inhibiting the formation of other trophoblast cell types by suppressing trophoblast progenitors and spongiotrophoblast-promoting factors, Eomes, Mash-2, and mSNA. Taken together with the spatial and temporal patterns of TGC formation and PTHrP synthesis in vivo, these findings indicate an important role for PTHrP in the differentiation of secondary TGCs during placentation.
El-Hashash
Ahmed H K
AH
Faculty of Life Sciences, University of Manchester, Oxford Road, Manchester M13 9PT, UK.
Esbrit
Pedro
P
Kimber
Susan J
SJ
D000818:Animals; D017209:Apoptosis; D051792:Basic Helix-Loop-Helix Proteins; D015415:Biomarkers / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation; D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation; D004261:DNA Replication; D004268:DNA-Binding Proteins / Q000032:analysis / Q000378:metabolism*; D005260:Female; D018507:Gene Expression Regulation, Developmental; D015726:Giant Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D018398:Homeodomain Proteins / Q000032:analysis / Q000378:metabolism*; D008297:Male; D051379:Mice; D044162:Parathyroid Hormone-Related Protein / Q000494:pharmacology / Q000502:physiology*; D010928:Placental Lactogen / Q000235:genetics / Q000378:metabolism; D044168:Receptor, Parathyroid Hormone, Type 1 / Q000032:analysis / Q000378:metabolism; D050656:Transcription Factor AP-2; D014157:Transcription Factors / Q000032:analysis / Q000378:metabolism*; D014327:Trophoblasts / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D015854:Up-Regulation
D051792:Basic Helix-Loop-Helix Proteins; D015415:Biomarkers; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; D044162:Parathyroid Hormone-Related Protein; D010928:Placental Lactogen; D044168:Receptor, Parathyroid Hormone, Type 1; D050656:Transcription Factor AP-2; D014157:Transcription Factors; C491539:Bhlhe40 protein, mouse; C583890:Tfap2c protein, mouse; C062303:placental lactogen II