Hypoxia Directs Human Extravillous Trophoblast Differentiation in a Hypoxia-Inducible Factor-Dependent Manner.
Villous cytotrophoblasts are epithelial stem cells of the early human placenta, able to differentiate either into syncytiotrophoblasts in floating chorionic villi or extravillous trophoblasts (EVTs) at the anchoring villi. The signaling pathways regulating differentiation into these two lineages are incompletely understood. The bulk of placental growth and development in the first trimester occurs under low oxygen tension. One major mechanism by which oxygen regulates cellular function is through the hypoxia-inducible factor (HIF), a transcription factor complex stabilized under low oxygen tension to mediate cellular responses, including cell fate decisions. HIF is known to play a role in trophoblast differentiation in rodents; however, its role in human trophoblast differentiation is poorly understood. Using RNA profiling of sorted populations of primary first-trimester trophoblasts, we evaluated the first stage of EVT differentiation, the transition from epidermal growth factor receptor+villous cytotrophoblasts into human leukocyte antigen-G+proximal column EVT (pcEVT) and identified hypoxia as a major pcEVT-associated pathway. Using primary cytotrophoblasts, we determined that culture in low oxygen directs differentiation preferentially toward human leukocyte antigen-G+pcEVT, and that an intact HIF complex is required for this process. Finally, using global RNA profiling, we identified integrin-linked kinase and associated cytoskeletal remodeling and adhesion to be among HIF-dependent pcEVT-associated signaling pathways. Taken together, we propose that oxygen regulates EVT differentiation through HIF-dependent modulation of various cell adhesion and morphology-related pathways.
Department of Pathology, University of California San Diego, La Jolla, California; Sanford Consortium for Regenerative Medicine, University of California San Diego, La Jolla, California.
Anna K
AK
Wakeland
Department of Pathology, University of California San Diego, La Jolla, California; Sanford Consortium for Regenerative Medicine, University of California San Diego, La Jolla, California.
Francesca
F
Soncin
Department of Pathology, University of California San Diego, La Jolla, California; Sanford Consortium for Regenerative Medicine, University of California San Diego, La Jolla, California.
Matteo
M
Moretto-Zita
Department of Pathology, University of California San Diego, La Jolla, California; Sanford Consortium for Regenerative Medicine, University of California San Diego, La Jolla, California.
Ching-Wen
CW
Chang
Department of Pathology, University of California San Diego, La Jolla, California; Sanford Consortium for Regenerative Medicine, University of California San Diego, La Jolla, California.
Mariko
M
Horii
Department of Pathology, University of California San Diego, La Jolla, California.
Don
D
Pizzo
Department of Pathology, University of California San Diego, La Jolla, California; Sanford Consortium for Regenerative Medicine, University of California San Diego, La Jolla, California.
Katharine K
KK
Nelson
Sanford Consortium for Regenerative Medicine, University of California San Diego, La Jolla, California; Department of Reproductive Medicine, University of California San Diego, La Jolla, California.
Louise C
LC
Laurent
Department of Pathology, University of California San Diego, La Jolla, California; Sanford Consortium for Regenerative Medicine, University of California San Diego, La Jolla, California. Electronic address: mparast@ucsd.edu.
Mana M
MM
Parast
D002454:Cell Differentiation; D015687:Cell Hypoxia / Q000235:genetics; D002469:Cell Separation; D002478:Cells, Cultured; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D051793:Hypoxia-Inducible Factor 1 / Q000378:metabolism*; D010100:Oxygen / Q000494:pharmacology; D011247:Pregnancy; D011261:Pregnancy Trimester, First / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D015203:Reproducibility of Results; D014157:Transcription Factors / Q000378:metabolism; D014327:Trophoblasts / Q000166:cytology* / Q000378:metabolism*; D015854:Up-Regulation / Q000235:genetics; D000099200:Scaffold Protein ILK
D051793:Hypoxia-Inducible Factor 1; D010100:Oxygen; D017346:Protein Serine-Threonine Kinases; D014157:Transcription Factors; D000099200:Scaffold Protein ILK