Aging is associated with reduced fitness and increased myeloid bias of the hematopoietic stem cell (HSC) compartment, causing increased risk of immune compromise, anemia, and malignancy. We show that mitochondrial membrane potential (MMP) can be used to prospectively isolate chronologically old HSCs with transcriptional features and functional attributes characteristic of young HSCs, including a high rate of transcription and balanced lineage-affiliated programs. Strikingly, MMP is a stronger determinant of the quantitative and qualitative transcriptional state of HSCs than chronological age, and transcriptional consequences of manipulation of MMP in HSCs within their native niche suggest a causal relationship. Accordingly, we show that pharmacological enhancement of MMP in old HSCs in vivo increases engraftment potential upon transplantation and reverses myeloid-biased peripheral blood output at steady state. Our results demonstrate that MMP is a source of heterogeneity in old HSCs, and its pharmacological manipulation can alter transcriptional programs with beneficial consequences for function.

衰老与适应性降低和造血干细胞（HSC）室的髓样偏见增加有关，导致免疫受损，贫血和恶性肿瘤的风险增加。我们表明，线粒体膜电位（MMP）可用于前瞻性地分离具有早期HSCs转录特性和功能属性特征的年代久远的HSC，包括高转录率和平衡的血统关联程序。令人惊讶的是，MMP是HSC定量和定性转录状态的决定因素，远比按年代顺序更重要，而且在其天然位点内操作MMP的HSC的转录结果表明存在因果关系。因此，我们显示了体内旧HSCs中MMP的药理作用增强增加了移植时的植入潜力，并在稳态下逆转了偏向骨髓的外周血输出。我们的结果表明，MMP是旧HSC中异质性的来源，其药理作用可以改变转录程序，并对功能产生有利影响。