Sun Ninghe, Lin Chun-Hsin, Li Michelle Y, Wang Yuting, Chen Danyang, Ren Xiangle, Zhang Feng, Zhang Yi
Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA, USA.
Division of Hematology/Oncology, Department of Pediatrics, Boston Children's Hospital, Boston, MA, USA.
Nat Aging. 2025 Jun 30. doi: 10.1038/s43587-025-00908-z.
Aged hematopoietic stem cells (HSCs) exhibit diminished self-renewal and myeloid-biased differentiation with a decline in hematopoiesis and adaptive immune function. However, the molecular regulation of this impaired function remains largely unknown. Here, through an in vivo CRISPR-Cas9-based screen, we uncovered clusterin (Clu) as a driver of biased differentiation. Clu is upregulated in aged HSCs, and its knockout diminishes biased differentiation. Clu promotes mitochondrial hyperfusion by interacting with Mfn2 in aged HSCs, and its ablation attenuates oxidative phosphorylation, improves mitophagy, and reverses myeloid-biased differentiation via the OXPHOS-p38-Cebpb axis. Transplantation of Clu-depleted aged HSCs into middle-aged mice results in balanced hematopoiesis and improved physical functions. Together, our data identify Clu as a critical regulator of aging-associated myeloid bias and reveal an Mfn2-OXPHOS-p38-Cebpb axis as the mechanism underlying how Clu upregulation in aged HSCs leads to myeloid-biased differentiation, providing a target for rejuvenation of aged hematopoietic and immune systems.
衰老的造血干细胞（HSCs）表现出自我更新能力减弱和髓系偏向性分化，同时造血功能和适应性免疫功能下降。然而，这种功能受损的分子调控机制在很大程度上仍不清楚。在这里，通过基于体内CRISPR-Cas9的筛选，我们发现簇集蛋白（Clu）是偏向性分化的驱动因子。Clu在衰老的造血干细胞中上调，其敲除可减少偏向性分化。在衰老的造血干细胞中，Clu通过与Mfn2相互作用促进线粒体过度融合，其缺失可减弱氧化磷酸化，改善线粒体自噬，并通过OXPHOS-p38-Cebpb轴逆转髓系偏向性分化。将Clu缺失的衰老造血干细胞移植到中年小鼠体内可导致造血平衡并改善身体功能。总之，我们的数据确定Clu是衰老相关髓系偏向性的关键调节因子，并揭示了Mfn2-OXPHOS-p38-Cebpb轴是衰老造血干细胞中Clu上调导致髓系偏向性分化的潜在机制，为衰老造血和免疫系统的年轻化提供了一个靶点。
