Molecular Medicine and Gene Therapy, Lund University, 22362 Lund, Sweden; Cancer Institute, University College London, London WC1E 6DD, United Kingdom.
Molecular Medicine and Gene Therapy, Lund University, 22362 Lund, Sweden.
Cell Stem Cell. 2021 Feb 4;28(2):241-256.e6. doi: 10.1016/j.stem.2020.09.018. Epub 2020 Oct 20.
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.
衰老是与造血干细胞（HSC）区的适应性降低和髓系偏向相关联的，这会导致免疫功能受损、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年轻 HSC 特征的转录特征和功能属性的时序上的老年 HSC，包括高转录率和平衡的谱系相关程序。引人注目的是，MMP 是决定 HSC 转录状态的数量和质量的一个比时间年龄更强的决定因素，并且在其天然生态位中对 HSC 中 MMP 的操纵的转录后果表明存在因果关系。因此，我们表明，在体内对老年 HSC 中 MMP 的药理学增强增加了移植后的植入潜力，并在稳定状态下逆转了骨髓偏向的外周血输出。我们的结果表明，MMP 是老年 HSC 异质性的一个来源，其药理学操作可以改变转录程序，从而对功能产生有益的影响。
