Role of CD38 in aging and rejuvenation of Hematopoietic stem cells
Final Report Abstract
Hematopoietic stem cells (HSCs) are rare cells continuously regenerating the entire hematopoietic system by producing billions of blood cells. A subpopulation of deeply quiescent, so-called dormant HSCs (dHSCs) represents a distinct HSC subpopulation characterized by deep quiescence and very low overall biosynthetic activity. dHSCs reside at the top of the hematopoietic hierarchy and serve as a stem cell reserve pool. The state of dormancy protects HSCs 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, using single-cell RNA sequencing, label retention assay, single-cell division tracking assay, several hematopoietic stress models, and serial transplantations, we identify CD38 as a novel and broadly applicable surface marker for the enrichment of murine dHSCs. Moreover, we uncovered the molecular mechanism promoting HSC dormancy. 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 Ca 2+ from the endoplasmic reticulum. Subsequently, we uncover that c-Fos induces the expression of the cell cycle inhibitor p57 Kip2 to drive HSC dormancy. Moreover, we identified that a similar mechanism is present in human HSCs: CD38 ecto-enzymatic activity at the neighbouring CD38-positive cells promotes human HSC quiescence, which are CD38 negative. Besides, several hematological malignancies (e.g. multiple myeloma, chronic lymphocytic leukemia, acute myeloid leukemia) express CD38 at a high level. We hypothesize that tumor microenvironment enriched in the products of CD38 ecto-enzymatic activity may suppress the cell cycle of healthy human HSCs, leading to cancer-related pancytopenia. Therefore, inhibiting CD38-mediated cADPR production might support healthy hematopoiesis in patients with hematologic malignancies. Together, pharmacological manipulations of CD38/cADPR/Ca2+/c-Fos/p57Kip2 pathway provide new strategies to improve the success of stem cell transplantation and blood regeneration after injury or disease.
Publications
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Profound sympathetic neuropathy in the bone marrow of patients with acute myeloid leukemia. Leukemia, 38(2), 393-397.
Kovtun, Iryna; von Bonin, Malte; Ibneeva, Liliia; Frimmel, Julia; Middeke, Jan Moritz; Kunadt, Desiree; Heberling, Lisa; Wobus, Manja; Bornhäuser, Martin & Grinenko, Tatyana
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CD38 promotes hematopoietic stem cell dormancy. PLOS Biology, 22(2), e3002517.
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
