Mitochondrial activity-driven hematopoietic stem cell fate and lympho-myeloid lineage choice is first established in the aorta-gonad-mesonephros

Mitochondrial metabolism determines bone marrow hematopoietic stem cell (HSC) heterogeneity and influences long-term repopulation potential. However, the origin of this heterogeneity and how it regulates HSC phenotype is unclear. We show that during the endothelial-to-hematopoietic transition (EHT) in the mouse embryo, dynamic changes in mitochondrial activity drive the production of mature HSCs with differing potencies. Lowering mitochondrial activity in the AGM by pharmacological or genetic means activates Wnt signaling to promote HSC expansion. Further, mitochondrial membrane potential (MMP) gives rise to functional heterogeneity in the definitive HSC pool. In-vitro and in-vivo functional assays, and single-cell transcriptomics on AGM HSCs showed that MMPlow HSCs are myeloid-biased, with enhanced differentiation potential, while MMPhigh HSCs are lymphoid-biased with diminished differentiation potential. Mechanistically, low mitochondrial activity upregulates Phosphoinositide 3-kinase (PI3K) signaling to promote HSC differentiation. These insights into the initiation of metabolic heterogeneity could be leveraged to isolate HSCs to efficiently generate desired lineages. HighlightsO_LIMitochondrial changes from HSC emergence to maturation govern embryonic hematopoiesis. C_LIO_LILowering mitochondrial activity promotes Wnt-dependent HSC expansion and PI3K-dependent differentiation. C_LIO_LIMitochondrial membrane potential determines lympho-myeloid fate choice in AGM HSCs. C_LIO_LIAberrant mitochondrial activity in the AGM HSCs perturbs adult hematopoiesis. C_LI O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=81 SRC="FIGDIR/small/609550v1_ufig1.gif" ALT="Figure 1"> View larger version (21K): org.highwire.dtl.DTLVardef@10ba1e2org.highwire.dtl.DTLVardef@b10b53org.highwire.dtl.DTLVardef@15eaad0org.highwire.dtl.DTLVardef@2077d5_HPS_FORMAT_FIGEXP M_FIG C_FIG