Miharada Kenichi, Sigurdsson Valgardur, Karlsson Stefan
Department for Molecular Medicine and Gene Therapy, Lund Strategic Center for Stem Cell Biology, Lund University, Lund 221 84, Sweden.
Department for Molecular Medicine and Gene Therapy, Lund Strategic Center for Stem Cell Biology, Lund University, Lund 221 84, Sweden.
Cell Rep. 2014 Jun 12;7(5):1381-1392. doi: 10.1016/j.celrep.2014.04.056. Epub 2014 May 29.
Developmental pluripotency-associated 5 (Dppa5) is an RNA binding protein highly expressed in undifferentiated pluripotent stem cells. Here, we demonstrate that Dppa5 is a regulator of hematopoietic stem cells (HSCs) that critically governs reconstitution capacity after bone marrow transplantation. Ectopic expression of Dppa5 followed by in vitro culture robustly increased HSC reconstitution levels through suppression of endoplasmic reticulum (ER) stress and apoptosis. Remarkably, a chemical chaperone that decreases ER stress in HSCs also increases HSC engraftment. Conversely, knockdown of Dppa5 impaired the long-term reconstitution ability of HSCs due to elevated ER stress levels, suggesting that ER stress regulation is physiologically important for proper HSC function in vivo. Thus, Dppa5 represents a pivotal connection between ER stress regulation and stem cell properties in HSCs. The findings also demonstrate that protein quality control is critical for the maintenance, survival, and function of HSCs in vivo and ex vivo.
发育多能性相关蛋白5（Dppa5）是一种在未分化的多能干细胞中高度表达的RNA结合蛋白。在此，我们证明Dppa5是造血干细胞（HSC）的一种调节因子，对骨髓移植后的重建能力起着关键的调控作用。Dppa5异位表达后进行体外培养，通过抑制内质网（ER）应激和细胞凋亡，有力地提高了造血干细胞的重建水平。值得注意的是，一种能降低造血干细胞内质网应激的化学伴侣也能增加造血干细胞的植入。相反，敲低Dppa5会因内质网应激水平升高而损害造血干细胞的长期重建能力，这表明内质网应激调节对体内造血干细胞的正常功能在生理上具有重要意义。因此，Dppa5代表了内质网应激调节与造血干细胞干细胞特性之间的关键联系。这些发现还表明，蛋白质质量控制对于体内和体外造血干细胞的维持、存活及功能至关重要。
