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Harnessing Autophagic Network Is Essential for Trophoblast Stem Cell Differentiation.
Stem Cells and Development ( IF 4 ) Pub Date : 2020-05-22 , DOI: 10.1089/scd.2019.0296
Shreeta Chakraborty 1 , Rumela Bose 1 , Safirul Islam 1 , Shreya Das 1 , Rupasri Ain 1
Affiliation  

Differentiation of trophoblast stem (TS) cells into various cell lineages of the placenta during mammalian development is accompanied by dynamic changes in its proteome for exerting the highly specialized functions of various cell subtypes. In the present study, we demonstrate that the autophagic machinery, which includes proteins for initiation, vesicle nucleation, and autophagosome maturation are robustly upregulated during differentiation of TS cells. Interestingly, basal levels of autophagy were detectable in the developing mouse placenta as well as TS cells. However, autophagic flux was actively triggered by induction of differentiation evident from LC3 maturation. Formation of Beclin1, Vps34, and PIK3R4 ternary complex at the phagophore assembly site that is typically known to induce autophagy was also enhanced during differentiation. Degradation of the p62/SQSTM1 cargo protein and its colocalization with LC3, a mature autophagosome marker, was most prevalent in the trophoblast giant cells (TGCs) and negligible in other trophoblast cells at day 6 of differentiation. Furthermore, disruption of autophagy by impairing lysosomal fusion in TS cells before induction of differentiation led to a decrease in the giant cell and spongiotrophoblast cell markers Prl3d1, Prl2c2, Prl4a1, and Tpbpα upon differentiation. In addition, inhibition of autophagy was associated with a decrease in nuclear size of TGCs. Taken together, these data highlight that autophagy is a necessary prelude in commitment of trophoblast differentiation from the multipotent TS cells probably by regulating protein turnover at the onset of differentiation.

中文翻译:

利用自噬网络对于滋养层干细胞分化至关重要。

在哺乳动物发育过程中,滋养层干细胞(TS)分化为胎盘的各种细胞谱系伴随着其蛋白质组的动态变化,以发挥各种细胞亚型的高度专门化功能。在本研究中,我们证明了自噬机制,包括用于启动,囊泡成核和自噬体成熟的蛋白质,在TS细胞分化过程中被强烈上调。有趣的是,在发育中的小鼠胎盘以及TS细胞中可检测到自噬的基础水平。然而,自噬通量是由LC3成熟明显诱导的分化诱导而主动触发的。Beclin1,Vps34和PIK3R4三元复合物在吞噬细胞组装位点(通常已知诱导自噬)的形成在分化过程中也得到增强。p62 / SQSTM1货物蛋白的降解及其与LC3(一种成熟的自噬体标记物)的共定位在滋养层巨细胞(TGC)中最普遍,在分化的第6天在其他滋养层细胞中可忽略不计。此外,在分化诱导之前,通过破坏TS细胞中的溶酶体融合来破坏自噬,导致巨细胞和海绵滋养细胞标志物减少分化后的Prl3d1,Prl2c2,Prl4a1Tpbpα。另外,自噬的抑制与TGCs核大小的减少有关。综上所述,这些数据突出表明自噬是从多能TS细胞分化为滋养层细胞的必要前奏,可能是通过在分化开始时调节蛋白质更新来实现的。
更新日期:2020-05-22
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