Mitochondrial Potentiation Ameliorates Age Related Heterogeneity in Hematopoietic Stem Cell Function [MMPhigh and MMPlow HSCs]

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. RNA seq of MMPhigh and MMPlow sorted HSCs from either young or old mice