Maintaining proteostasis is key to resisting stress and promoting healthy aging. Proteostasis is necessary to preserve stem cell function, but little is known about the mechanisms that regulate proteostasis during stress in stem cells, and whether disruptions of proteostasis contribute to stem cell aging is largely unexplored. We determined that ex-vivo-cultured mouse and human hematopoietic stem cells (HSCs) rapidly increase protein synthesis. This challenge to HSC proteostasis was associated with nuclear accumulation of Hsf1, and deletion of Hsf1 impaired HSC maintenance ex vivo. Strikingly, supplementing cultures with small molecules that enhance Hsf1 activation partially suppressed protein synthesis, rebalanced proteostasis, and supported retention of HSC serial reconstituting activity. Although Hsf1 was dispensable for young adult HSCs in vivo, Hsf1 deficiency increased protein synthesis and impaired the reconstituting activity of middle-aged HSCs. Hsf1 thus promotes proteostasis and the regenerative activity of HSCs in response to culture stress and aging.

维持蛋白质稳态是抵抗压力和促进健康衰老的关键。蛋白质稳态是保持干细胞功能所必需的，但对于在干细胞应激期间调节蛋白质稳态的机制知之甚少，以及蛋白质稳态的破坏是否会导致干细胞衰老在很大程度上尚未得到探索。我们确定离体培养的小鼠和人类造血干细胞 (HSC) 会迅速增加蛋白质合成。这种对 HSC 蛋白质稳态的挑战与 Hsf1 的核积累有关，而 Hsf1 的缺失损害了离体HSC 的维持. 引人注目的是，用增强 Hsf1 活化的小分子补充培养物可部分抑制蛋白质合成，重新平衡蛋白质稳态，并支持 HSC 系列重组活性的保留。尽管Hsf1在体内对年轻成人 HSC 来说是可有可无的，但 Hsf1缺乏会增加蛋白质合成并损害中年 HSC 的重建活性。因此，Hsf1 促进了 HSC 的蛋白质稳态和再生活性，以应对培养压力和衰老。