Cinkornpumin Jessica K, Kwon Sin Young, Prandstetter Anna-Maria, Maxian Theresa, Sirois Jacinthe, Goldberg James, Zhang Joy, Saini Deepak, Dasgupta Purbasa, Jeyarajah Mariyan J, Renaud Stephen J, Paul Soumen, Haider Sandra, Pastor William A
Department of Biochemistry, McGill University, Montreal, QC, Canada.
Placental Development Group, Reproductive Biology Unit, Medical University of Vienna, Vienna, Austria.
Stem Cell Reports. 2025 May 13;20(5):102481. doi: 10.1016/j.stemcr.2025.102481. Epub 2025 Apr 24.
During the first stages of embryonic development, the placenta develops under very low oxygen tension (∼1%-2% O), so we sought to determine the regulatory role of oxygen in human trophoblast stem cells (hTSCs). We find that low oxygen promotes hTSC self-renewal but inhibits differentiation to syncytiotrophoblast (STB) and extravillous trophoblast (EVT). The transcription factor GCM1 (glial cell missing transcription factor 1) is downregulated in low oxygen, and concordantly, there is substantial reduction of GCM1-regulated genes in hypoxic conditions. Knockout of GCM1 in hTSC likewise impaired EVT and STB formation. Treatment with a phosphatidylinositol 3-kinase (PI3K) inhibitor reported to reduce GCM1 protein levels likewise counteracts spontaneous or directed differentiation. Additionally, chromatin immunoprecipitation of GCM1 showed binding near key genes upregulated upon differentiation including the contact inhibition factor CDKN1C. Loss of GCM1 resulted in downregulation of CDKN1C and corresponding loss of contact inhibition, implicating GCM1 in regulation of this critical process.
在胚胎发育的最初阶段，胎盘是在极低的氧张力（约1%-2% O₂）下发育的，因此我们试图确定氧在人滋养层干细胞（hTSCs）中的调节作用。我们发现低氧促进hTSC自我更新，但抑制其向合体滋养层（STB）和绒毛外滋养层（EVT）的分化。转录因子GCM1（神经胶质缺失转录因子1）在低氧条件下表达下调，相应地，在缺氧条件下GCM1调控的基因也大幅减少。在hTSC中敲除GCM1同样会损害EVT和STB的形成。用据报道可降低GCM1蛋白水平的磷脂酰肌醇3激酶（PI3K）抑制剂处理同样会抵消自发或定向分化。此外，GCM1的染色质免疫沉淀显示其在分化时上调的关键基因附近结合，包括接触抑制因子CDKN1C。GCM1的缺失导致CDKN1C下调以及相应的接触抑制丧失，这表明GCM1参与了这一关键过程的调节。
