Saghi Ghaffari课题组在研究中取得进展。他们报道了逆转溶酶体功能障碍恢复衰老造血干细胞的年轻状态。该项研究成果发表在2025年11月24日出版的《细胞—干细胞》上。

该研究团队发现，衰老的造血干细胞中的溶酶体是高酸性的、耗尽的、受损的和异常激活的。单细胞转录组学和功能分析表明，抑制以空泡型ATP酶（v-ATP酶）抑制剂为中心的高活化溶酶体可恢复衰老造血干细胞中溶酶体的完整性、代谢和表观遗传稳态。这种干预通过改善线粒体DNA的溶酶体加工和减弱环GMP-AMP合成酶刺激干扰素基因（cGAS-STING）信号传导来减少炎症和干扰素驱动程序。引人注目的是，体外溶酶体抑制使衰老hsc的体内再生能力提高了8倍以上，并提高了它们的自我更新能力。因此，溶酶体功能障碍成为HSC衰老的关键驱动因素。靶向过度激活的溶酶体可以恢复老年造血干细胞的年轻状态，为恢复老年人造血功能提供了一种有希望的策略。

据悉，衰老损害造血干细胞（HSCs），驱动克隆造血、髓系恶性肿瘤和免疫衰退。溶酶体在HSC衰老中的作用——除了它们被动介导自噬之外——尚不清楚。

附：英文原文

Title: Reversing lysosomal dysfunction restores youthful state in aged hematopoietic stem cells

Author: Tasleem Arif, Jiajing Qiu, Hossein Khademian, Anusree Lohithakshan, Anagha Menon, Vijay Menon, Mary Slavinsky, Maxime Batignes, Miao Lin, Robert Sebra, Kristin G. Beaumont, Deanna L. Benson, Nikolaos Tzavaras, Mickal M. Ménager, Saghi Ghaffari

Issue&Volume: 2025-11-24

Abstract: Aging impairs hematopoietic stem cells (HSCs), driving clonal hematopoiesis, myeloid malignancies, and immune decline. The role of lysosomes in HSC aging—beyond their passive mediation of autophagy—is unclear. We show that lysosomes in aged HSCs are hyperacidic, depleted, damaged, and aberrantly activated. Single-cell transcriptomics and functional analyses reveal that suppression of hyperactivated lysosomes using a vacuolar ATPase (v-ATPase) inhibitor restores lysosomal integrity and metabolic and epigenetic homeostasis in old HSCs. This intervention reduces inflammatory and interferon-driven programs by improving lysosomal processing of mitochondrial DNA and attenuating cyclic GMP-AMP synthase-stimulator of interferon gene (cGAS-STING) signaling. Strikingly, ex vivo lysosomal inhibition boosts old HSCs’ in vivo repopulation capacity by over eightfold and improves their self-renewal. Thus, lysosomal dysfunction emerges as a key driver of HSC aging. Targeting hyperactivated lysosomes reinstates a youthful state in old HSCs, offering a promising strategy to restore hematopoietic function in the elderly.

DOI: 10.1016/j.stem.2025.10.012

Source: https://www.cell.com/cell-stem-cell/abstract/S1934-5909(25)00405-9