PDF(Pubmed)
Abstract：
Demand-adjusted and cell type specific rates of protein synthesis represent an important safeguard for fate and function of long-term hematopoietic stem cells. Here, we identify increased protein synthesis rates in the fetal hematopoietic stem cell pool at the onset of hematopoietic failure in Fanconi Anemia, a prototypical DNA repair disorder that manifests with bone marrow failure. Mechanistically, the accumulation of misfolded proteins in Fancd2-/- fetal liver hematopoietic stem cells converges on endoplasmic reticulum stress, which in turn constrains midgestational expansion. Restoration of protein folding by the chemical chaperone tauroursodeoxycholic acid, a hydrophilic bile salt, prevents accumulation of unfolded proteins and rescues Fancd2-/- fetal liver long-term hematopoietic stem cell numbers. We find that proteostasis deregulation itself is driven by excess sterile inflammatory activity in hematopoietic and stromal cells within the fetal liver, and dampened Type I interferon signaling similarly restores fetal Fancd2-/- long-term hematopoietic stem cells to wild type-equivalent numbers. Our study reveals the origin and pathophysiological trigger that gives rise to Fanconi anemia hematopoietic stem cell pool deficits. More broadly, we show that fetal protein homeostasis serves as a physiological rheostat for hematopoietic stem cell fate and function.
摘要：
蛋白质合成的需求调整率和细胞类型特异性率代表了长期造血干细胞命运和功能的重要保障。这里,我们发现Fanconi贫血发生造血衰竭时胎儿造血干细胞池的蛋白质合成率增加，典型的DNA修复障碍，表现为骨髓衰竭。机械上,Fancd2-/-胎肝造血干细胞中错误折叠蛋白的积累集中于内质网应激，这反过来又限制了妊娠中期的扩张。通过化学伴侣牛磺熊去氧胆酸恢复蛋白质折叠，一种亲水的胆汁盐，防止未折叠蛋白质的积累，并挽救Fancd2-/-胎儿肝脏的长期造血干细胞数量。我们发现，蛋白质平衡失调本身是由胎儿肝脏内造血和基质细胞中过量的无菌炎症活性驱动的，和抑制的I型干扰素信号传导类似地将胎儿Fancd2-/-长期造血干细胞恢复到野生型等效数量。我们的研究揭示了导致范可尼贫血造血干细胞池缺陷的起源和病理生理触发因素。更广泛地说,我们证明胎儿蛋白稳态是造血干细胞命运和功能的生理变阻器。
