Bile Acids Protect Expanding Hematopoietic Stem Cells from Unfolded Protein Stress in Fetal Liver
Bile Acids Protect Expanding Hematopoietic Stem Cells from Unfolded Protein Stress in Fetal Liver
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DOI：
10.1016/j.stem.2016.01.002
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发表时间：
2016-04-07
期刊：
影响因子：
23.9
通讯作者：
Miharada, Kenichi
中科院分区：
文献类型：
--
作者：
Sigurdsson, Valgardur;Takei, Hajime;Miharada, Kenichi
在发育过程中，造血干细胞（HSCs）在胚胎肝脏（FL）中经历快速扩增，然后定居在成人骨髓中。我们最近报道，增殖的成体HSC容易受到错误折叠蛋白积累引起的ER应激的影响。在这里，我们发现，FL-HSC，尽管增加了蛋白质合成速率和蛋白质折叠的要求，不上调ER分子伴侣。相反，从母体和胎儿肝脏分泌的胆汁酸（BA）协调充当化学伴侣。牛磺胆酸是FL中的主要BA，通过抑制蛋白质聚集来支持HSC的体外生长。在体内，降低BA水平导致ER应激升高和聚集蛋白的积累，并显著降低FL-HSC的数量。总之，这些发现表明，BA缓解ER应激是胎儿造血过程中HSC扩增所需的机制。
Duringdevelopment, hematopoietic stemcells (HSCs) undergo a rapid expansion in the fetal liver (FL) before settling in the adult bone marrow. We recently reported that proliferating adult HSCs are vulnerable to ER stress caused by accumulation of mis-folded proteins. Here, we find that FL-HSCs, despite an increased protein synthesis rate and a requirement for protein folding, do not upregulate ER chaperones. Instead, bile acids (BAs), secreted from maternal and fetal liver, coordinate to serve as chemical chaperones. Taurocholic acid, the major BA in FL, supports growth of HSCs in vitro by inhibiting protein aggregation. In vivo, reducing BA levels leads to ER stress elevation and accumulation of aggregated proteins and significantly decreases the number of FL-HSCs. Taken together, these findings reveal that BA alleviation of ER stress is a mechanism required for HSC expansion during fetal hematopoiesis.