Mitochondria-enriched hematopoietic stem cells exhibit elevated self-renewal capabilities, thriving within the context of aged bone marrow [bulk RNA-seq]

The aging of hematopoietic stem cells (HSCs) significantly alters their characteristics. Mitochondria, essential for cellular metabolism, play a crucial role, and their dysfunction is a hallmark of aging-induced changes. The impact of mitochondrial mass on aged HSCs remains incompletely understood. Here, we demonstrate that HSCs with high mitochondrial mass during aging are not merely cells that have accumulated damaged mitochondria and become exhausted. Instead, these HSCs retain a high regenerative capacity and remain in the aging bone marrow. Furthermore, we identified GPR183 as a novel marker characterizing aged HSCs through single-cell analysis. HSCs marked by GPR183 were also enriched in aged HSCs with high mitochondrial mass, possessing a high capacity of self-renewal. These insights deepen our understanding of HSC aging and provide new perspectives on the assessment of aged HSCs, underscoring the importance of mitochondrial dynamics in the aging. Overall design: Bulk RNA-seq of LT-HSCs, ST-HSCs, and MPPs of 4 young (12 weeks old) and 4 aged (107 weeks old) male mice

造血干细胞（hematopoietic stem cells, HSCs）的衰老会显著改变其生物学特性。线粒体作为细胞代谢的核心必需组分，发挥关键调控作用，其功能失调是衰老诱导的细胞改变的标志性特征。然而线粒体质量对衰老造血干细胞的影响机制仍未完全阐明。

本研究证实，衰老过程中线粒体质量较高的造血干细胞并非仅为积累了损伤线粒体并发生功能耗竭的细胞群体。相反，这类造血干细胞仍保留极强的造血重建能力，并持续存在于衰老的骨髓微环境中。此外，我们通过单细胞分析鉴定出GPR183可作为衰老造血干细胞的新型标志物。表达GPR183的造血干细胞同样富集于线粒体质量较高的衰老造血干细胞群体中，具备优异的自我更新能力。

上述研究结果深化了我们对造血干细胞衰老机制的认知，为衰老造血干细胞的评估提供了全新视角，凸显了线粒体动态平衡在衰老进程中的重要意义。

总体实验设计：对4只年轻（12周龄）及4只衰老（107周龄）雄性小鼠的长期造血干细胞（long-term hematopoietic stem cells, LT-HSCs）、短期造血干细胞（short-term hematopoietic stem cells, ST-HSCs）及多能祖细胞（multipotent progenitors, MPPs）开展批量RNA测序（Bulk RNA-seq）。