@article{TEXTUAL,
      recid = {11279},
      author = {Kovuru, Narasaiah and Mochizuki-Kashio, Makiko and Menna,  Theresa and Jeffrey, Greer and Hong, Yuning and Yoon, Young  me and Zhang, Zhe and Kurre, Peter},
      title = {Deregulated protein homeostasis constrains fetal  hematopoietic stem cell pool expansion in Fanconi anemia},
      journal = {Nature Communications},
      address = {2024-02-29},
      number = {TEXTUAL},
      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<sup>−/−</sup> 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<sup>−/−</sup> 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<sup>−/−</sup> 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.},
      url = {http://knowledge.uchicago.edu/record/11279},
}