Restraining Lysosomal Activity Preserves Hematopoietic Stem Cell Quiescence and Potency

Raymond Liang, Tasleem Arif, Svetlana Kalmykova, Artem Kasianov, Miao Lin, Vijay Menon, Jiajing Qiu, Jeffrey M. Bernitz, Kateri Moore, Fangming Lin, Deanna L. Benson, Nikolaos Tzavaras, Milind Mahajan, Dmitri Papatsenko, Saghi Ghaffari

Research output: Contribution to journalArticlepeer-review

77 Scopus citations

Abstract

Quiescence is a fundamental property that maintains hematopoietic stem cell (HSC) potency throughout life. Quiescent HSCs are thought to rely on glycolysis for their energy, but the overall metabolic properties of HSCs remain elusive. Using combined approaches, including single-cell RNA sequencing (RNA-seq), we show that mitochondrial membrane potential (MMP) distinguishes quiescent from cycling-primed HSCs. We found that primed, but not quiescent, HSCs relied readily on glycolysis. Notably, in vivo inhibition of glycolysis 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 in HSCs led to further enlargement of lysosomes while suppressing 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 preserves HSC quiescence and potency and may be therapeutically relevant. The quiescence and potency of hematopoietic stem cells (HSCs) are thought to be maintained by glycolysis. By exploiting mitochondrial heterogeneity, Liang, Arif, et al. uncover that activated, but not quiescent, HSCs use glycolysis for energy. Quiescence is maintained by an abundance of lysosomes whose repression enhances HSC potency by over 90-fold.

Original languageEnglish
Pages (from-to)359-376.e7
JournalCell Stem Cell
Volume26
Issue number3
DOIs
StatePublished - 5 Mar 2020
Externally publishedYes

Keywords

  • HSC
  • dormancy
  • fission
  • hematopoietic stem cell
  • label retention
  • lysosomes
  • mTOR
  • mitochondria
  • mitophagy
  • quiescence

ASJC Scopus subject areas

  • Molecular Medicine
  • Genetics
  • Cell Biology

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