CD38 promotes hematopoietic stem cell dormancy

• Published in: PLoS biology Vol. 22; no. 2; p. e3002517
• Main Authors: Ibneeva, Liliia, Singh, Sumeet Pal, Sinha, Anupam, Eski, Sema Elif, Wehner, Rebekka, Rupp, Luise, Kovtun, Iryna, Pérez-Valencia, Juan Alberto, Gerbaulet, Alexander, Reinhardt, Susanne, Wobus, Manja, von Bonin, Malte, Sancho, Jaime, Lund, Frances, Dahl, Andreas, Schmitz, Marc, Bornhäuser, Martin, Chavakis, Triantafyllos, Wielockx, Ben, Grinenko, Tatyana
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 29.02.2024; Public Library of Science (PLoS)
• Subjects: Adenosine diphosphate; Analysis; Animals; Biology and Life Sciences; c-Fos protein; Calcium (reticular); Calcium - metabolism; Calcium ions; CD38 antigen; Cell cycle; Cyclic ADP-ribose; Cyclic ADP-Ribose - metabolism; Dormancy; Dormancy (Biology); Endoplasmic reticulum; Enzymatic activity; Gene expression; Glycoproteins; Hematopoietic Stem Cells; Humans; Identification and classification; Influence; Medicine and Health Sciences; Mice; Research and Analysis Methods; Ribose; Ryanodine Receptor Calcium Release Channel - metabolism; Stem cell transplantation; Stem cells; Surface markers; China
• ISSN: 1545-7885; 1544-9173; 1545-7885
• DOI: 10.1371/journal.pbio.3002517

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.