A latent subset of human hematopoietic stem cells resists regenerative stress to preserve stemness

Kerstin B. Kaufmann, Andy G.X. Zeng, Etienne Coyaud, Laura Garcia-Prat, Efthymia Papalexi, Alex Murison, Estelle M.N. Laurent, Michelle Chan-Seng-Yue, Olga I. Gan, Kristele Pan, Jessica McLeod, Héléna Boutzen, Sasan Zandi, Shin ichiro Takayanagi, Rahul Satija, Brian Raught, Stephanie Z. Xie, John E. Dick

Research output: Contribution to journalArticlepeer-review


Continuous supply of immune cells throughout life relies on the delicate balance in the hematopoietic stem cell (HSC) pool between long-term maintenance and meeting the demands of both normal blood production and unexpected stress conditions. Here we identified distinct subsets of human long-term (LT)-HSCs that responded differently to regeneration-mediated stress: an immune checkpoint ligand CD112lo subset that exhibited a transient engraftment restraint (termed latency) before contributing to hematopoietic reconstitution and a primed CD112hi subset that responded rapidly. This functional heterogeneity and CD112 expression are regulated by INKA1 through direct interaction with PAK4 and SIRT1, inducing epigenetic changes and defining an alternative state of LT-HSC quiescence that serves to preserve self-renewal and regenerative capacity upon regeneration-mediated stress. Collectively, our data uncovered the molecular intricacies underlying HSC heterogeneity and self-renewal regulation and point to latency as an orchestrated physiological response that balances blood cell demands with preserving a stem cell reservoir.

Original languageEnglish (US)
Pages (from-to)723-734
Number of pages12
JournalNature Immunology
Issue number6
StatePublished - Jun 2021

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology


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