Mitochondrial Potentiation Ameliorates Age Related Heterogeneity in Hematopoietic Stem Cell Function [HSCs treated]

introduction: Ageing 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 results: 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 programmes. 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. conclusion: 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. Overall design: RNA seq of Old HSCs compared to Young HSCs as well as Old HSCs from Mito-Q treated mice and young HSCs from CCCP treated mice