Mitochondrial Potentiation Ameliorates Age-Related Heterogeneity in Hematopoietic Stem Cell Function

•HSCs from old and young mice are heterogeneous for mitochondrial activity (MMP)•MMPhigh HSCs have young-like transcriptional functional features•MMP of can be manipulated in vivo with consequences function•Mitochondrial potentiation prevent or ameliorate onset hematopoietic aging Aging is associated reduced fitness increased myeloid bias the stem cell (HSC) compartment, causing risk immune compromise, anemia, malignancy. We show that membrane potential (MMP) used to prospectively isolate chronologically features attributes characteristic HSCs, including a high rate transcription balanced lineage-affiliated programs. Strikingly, MMP stronger determinant quantitative qualitative state than chronological age, manipulation within their native niche suggest causal relationship. Accordingly, we pharmacological enhancement increases engraftment upon transplantation reverses myeloid-biased peripheral blood output at steady state. 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Finally, pharmacologically enhanced function, indicated transplantation. steady-state setting, mitochondrial-targeted treatment causes rescue lympho-erythroid highlighting translational our findings. parameters apply organism. Staining (mitotracker green [MTG]) (Tetramethylrhodamine methyl ester [TMRM], DilC1(5), Tetramethylrhodamine ethyl [TMRE], JC-1) presence VP combined panel discriminate stem, progenitor, compartments (Figure 1A). line published literature, observed significant increase immunophenotypic expense compartment-1 (HPC1) first validated effect dye retention versus cells; MTG (Norddahl Scholar) recently TMRM (Bonora DilC1(5) TMRE. absence VP, primitive (Lin- Sca1+ cKit+; LSK) particular appear lower (Lin+) animals S1A). recent report (Liang Scholar), inclusion significantly staining intensity without affecting total (Figures 1B, S1B, S1C); thus, throughout study. accordance related data confirm indeed relative trend 1C S1D). saw marked reduction progenitors, pronouncedly 1D S1E); this any major change measured 1D) quantifications nuclear ratio (data shown), indicating per-mitochondrial distribution values showed covered broadly 1E). difference average value seen level end range, while center end. categorized MMPhigh MMPlow splitting components centered around median (MFI) combined, allowing gap spans least 15% each sample. 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Iida Nittono Miharada Bile Acids Protect Expanding Unfolded Protein Stress Fetal Liver.Cell 18: 522-532Abstract (57) Figures 2C S2B). 2D, S2B, S2C). Fluorescence-activated sorting (FACS) shows they 2E Classification “fast” (orange) “slow” (gray) small percentage transcribes 2E). To connection further, sorted HSPCs after labeled 5-EU analyzed rate. 2F S2D). further validate HSPCs, performed critical mRNA subunits polymerase (RNA Pol II) (Polr2a,e) elongation Ell2, MMPhighsorted