缺氧和 GCM1 表达缺失可防止人类滋养层干细胞分化和接触抑制

Jessica K. Cinkornpumin, Sin Young Kwon, Anna-Maria Prandstetter, Theresa Maxian, Jacinthe Sirois, James Goldberg, Joy Zhang, Deepak Saini, Purbasa Dasgupta, Mariyan J. Jeyarajah, Stephen Renaud, Soumen Paul, Sandra Haider, William A Pastor
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摘要

胎盘与胚胎一起发育,孕育胎儿发育至足月。在胚胎发育的最初阶段,由于血液循环不畅,血液和环境中的氧气供应量非常低(~1-2% O2),胎盘侵入后氧气供应量逐渐增加。虽然缺氧环境与干细胞自我更新和增殖有关,但持续缺氧可能对分化细胞产生严重影响,并可能成为胎盘疾病的根本原因。我们发现,人类滋养层干细胞(hTSC)在低氧条件下茁壮成长,而hTSC向滋养层细胞、合体滋养层细胞(STB)和体外滋养层细胞(EVT)的分化则受到缺氧条件的负面影响。促分化因子 GCM1(人神经胶质细胞缺失-1)在低氧条件下下调,同时 GCM1 调控的基因在低氧条件下大量减少。在 hTSC 中敲除 GCM1 会导致 EVT 和 STB 的形成和功能受损,减少分化反应基因的表达,并导致自我更新基因的维持。据报道,用 PI3K 抑制剂处理可降低 GCM1 蛋白水平,同样可抵消自发或定向分化。此外,GCM1 的染色质免疫沉淀显示,GCM1 特异性结合富集在分化时上调的关键转录因子附近,包括接触抑制因子 CDKN1C。GCM1 的缺失导致 CDKN1C 的下调和相应的接触抑制的缺失,这表明 GCM1 参与了这一关键过程的调控。
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Hypoxia and loss of GCM1 expression prevents differentiation and contact inhibition in human trophoblast stem cells
The placenta develops alongside the embryo and nurtures fetal development to term. During the first stages of embryonic development, due to low blood circulation, the blood and ambient oxygen supply is very low (~1-2% O2) and gradually increases upon placental invasion. While a hypoxic environment is associated with stem cell self-renewal and proliferation, persistent hypoxia may have severe effects on differentiating cells and could be the underlying cause of placental disorders. We find that human trophoblast stem cells (hTSC) thrive in low oxygen, whereas differentiation of hTSC to trophoblast to syncytiotrophoblast (STB) and extravillous trophoblast (EVT) is negatively affected by hypoxic conditions. The pro-differentiation factor GCM1 (human Glial Cell Missing-1) is downregulated in low oxygen, and concordantly there is substantial reduction of GCM1-regulated genes in hypoxic conditions. Knockout of GCM1 in hTSC caused impaired EVT and STB formation and function, reduced expression of differentiation-responsive genes, and resulted in maintenance of self-renewal genes. Treatment with a PI3K inhibitor reported to reduce GCM1 protein levels likewise counteracts spontaneous or directed differentiation. Additionally, chromatin immunoprecipitation of GCM1 showed enrichment of GCM1-specific binding near key transcription factors 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.
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