A single hematopoietic stem cell (HSC) is capable of reconstituting hematopoiesis and maintaining homeostasis by balancing self-renewal and cell differentiation. The mechanisms of HSC division balance, however, are not yet defined. Here we demonstrate, by characterizing at the single cell level a purified and minimally heterogeneous Tie2+ HSC population, that these top hierarchical HSCs preferentially undergo symmetric divisions. The induction of mitophagy, a quality-control process in mitochondria, plays an essential role in self-renewing expansion of Tie2+ HSCs. Activation of PPAR-fatty acid oxidation promotes to expand Tie2+ HSCs through enhanced Parkin recruitment in mitochondria. These metabolic pathways are conserved in human TIE2+ HSCs. Our data thus identify mitophagy as a key mechanisms of HSC expansion, and suggest potential methods of cell fate manipulation through metabolic pathways.
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