Project name: Mitochondrial hetereogeneity in hematopoietic stem cells (HSC)

Description: Quiescence is a fundamental property that maintains hematopoietic stem cells (HSCs)’ potency throughout life. Quiescent HSCs are thought to rely on glycolysis for their energy but the overall metabolic properties of HSCs remain incompletely understood. Using combined approaches including single cell RNA-Seq we show that mitochondrial membrane potential (MMP) distinguishes the quiescent from cycling-primed HSCs. We found that primed but not quiescent HSCs relied readily on glycolysis. Notably, in vivo inhibition of glycolysis robustly enhanced the competitive repopulation ability of primed HSCs. We further show that HSC quiescence is maintained by an abundance of large lysosomes. Repression of lysosomal activation led to further enlargement of lysosomes, while repressing mTOR activation and glucose uptake. This also induced increased lysosomal sequestration of mitochondria and enhanced the competitive repopulation ability of primed HSCs by over 90-fold in vivo. These findings show that restraining lysosomal activity is key in preserving HSC quiescence and potency, and may be therapeutically relevant.Overall design: To elucidate the potential diversity of cellular identity at the single cell level in quiescent mitochondrial membrane potential (MMP)-low versus primed MMP-high HSCs we used single-cell RNA-Seq (scRNA-Seq). Using the Fluidigm C1 platform, a total of 122 MMP-low HSCs and 126 MMP-high HSCs were deemed healthy after FACS purification and subsequently sequenced. A total of 224 cells were included for further analysis after the reads were mapped, processed, and filtered (>600,000 reads, >5,500 genes detected).

Data type: Transcriptome or Gene expression

Sample scope: Multiisolate

Relevance: ModelOrganism

Last updated: 2019-12-04