Hypoxia Directs Human Extravillous Trophoblast Differentiation in a Hypoxia-Inducible Factor–Dependent Manner
0301 basic medicine
1.1 Normal biological development and functioning
Cells
Cell Separation
Protein Serine-Threonine Kinases
Medical and Health Sciences
03 medical and health sciences
Stem Cell Research - Nonembryonic - Human
Underpinning research
Pregnancy
Pathology
Humans
First
Cells, Cultured
Cultured
Gene Expression Profiling
Reproducibility of Results
Cell Differentiation
Stem Cell Research
Cell Hypoxia
Trophoblasts
Up-Regulation
3. Good health
Oxygen
Pregnancy Trimester, First
Female
Pregnancy Trimester
Hypoxia-Inducible Factor 1
Transcription Factors
DOI:
10.1016/j.ajpath.2016.11.018
Publication Date:
2017-02-04T12:17:55Z
AUTHORS (9)
ABSTRACT
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.
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