Laboratory of Normal and Pathological Homeostasis of the Immune System, INSERM UMR 1163, Imagine Institute, Paris.
Université Paris Descartes -Sorbonne Paris Cité, Imagine Institute, Paris.
Haematologica. 2020 Jan;105(1):59-70. doi: 10.3324/haematol.2018.207100. Epub 2019 Apr 19.
The molecular machinery that regulates the balance between self-renewal and differentiation properties of hematopoietic stem cells (HSC) has yet to be characterized in detail. Here we found that the tetratricopeptide repeat domain 7 A (Ttc7a) protein, a putative scaffold protein expressed by HSC, acts as an intrinsic regulator of the proliferative response and the self-renewal potential of murine HSC Loss of Ttc7a consistently enhanced the competitive repopulating ability of HSC and their intrinsic capacity to replenish the hematopoietic system after serial cell transplantations, relative to wildtype cells. Ttc7a-deficient HSC exhibit a different transcriptomic profile for a set of genes controlling the cellular response to stress, which was associated with increased proliferation in response to chemically induced stress and myeloablative stress Our results therefore revealed a previously unrecognized role of Ttc7a as a critical regulator of HSC stemness. This role is related, at least in part, to regulation of the endoplasmic reticulum stress response.
调控造血干细胞（HSC）自我更新和分化特性之间平衡的分子机制尚未得到详细描述。在这里，我们发现四肽重复结构域 7A（Ttc7a）蛋白是一种由 HSC 表达的假定支架蛋白，作为内在调节因子，调节了小鼠 HSC 的增殖反应和自我更新潜能。与野生型细胞相比，Ttc7a 的缺失一致增强了 HSC 的竞争重编程能力及其在连续细胞移植后补充造血系统的内在能力。Ttc7a 缺陷型 HSC 表现出一套控制细胞对应激反应的基因的不同转录组谱，这与对化学诱导应激和骨髓清除性应激的增殖反应增加有关。因此，我们的研究结果揭示了 Ttc7a 作为 HSC 干性关键调节因子的先前未被认识的作用。这种作用至少部分与内质网应激反应的调节有关。
