PLoS Biology (Feb 2024)

CD38 promotes hematopoietic stem cell dormancy.

  • Liliia Ibneeva,
  • Sumeet Pal Singh,
  • Anupam Sinha,
  • Sema Elif Eski,
  • Rebekka Wehner,
  • Luise Rupp,
  • Iryna Kovtun,
  • Juan Alberto Pérez-Valencia,
  • Alexander Gerbaulet,
  • Susanne Reinhardt,
  • Manja Wobus,
  • Malte von Bonin,
  • Jaime Sancho,
  • Frances Lund,
  • Andreas Dahl,
  • Marc Schmitz,
  • Martin Bornhäuser,
  • Triantafyllos Chavakis,
  • Ben Wielockx,
  • Tatyana Grinenko

DOI
https://doi.org/10.1371/journal.pbio.3002517
Journal volume & issue
Vol. 22, no. 2
p. e3002517

Abstract

Read online

A subpopulation of deeply quiescent, so-called dormant hematopoietic stem cells (dHSCs) resides at the top of the hematopoietic hierarchy and serves as a reserve pool for HSCs. The state of dormancy protects the HSC pool from exhaustion throughout life; however, excessive dormancy may prevent an efficient response to hematological stresses. Despite the significance of dHSCs, the mechanisms maintaining their dormancy remain elusive. Here, we identify CD38 as a novel and broadly applicable surface marker for the enrichment of murine dHSCs. We demonstrate that cyclic adenosine diphosphate ribose (cADPR), the product of CD38 cyclase activity, regulates the expression of the transcription factor c-Fos by increasing the release of Ca2+ from the endoplasmic reticulum (ER). Subsequently, we uncover that c-Fos induces the expression of the cell cycle inhibitor p57Kip2 to drive HSC dormancy. Moreover, we found that CD38 ecto-enzymatic activity at the neighboring CD38-positive cells can promote human HSC quiescence. Together, CD38/cADPR/Ca2+/c-Fos/p57Kip2 axis maintains HSC dormancy. Pharmacological manipulations of this pathway can provide new strategies to improve the success of stem cell transplantation and blood regeneration after injury or disease.