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
Institute for Clinical Chemistry and Laboratory Medicine, University Hospital and Faculty of Medicine, Technische Universität Dresden, Dresden, Germany.
IRIBHM, Université Libre de Bruxelles (ULB), Brussels, Belgium.
PLoS Biol. 2024 Feb 29;22(2):e3002517. doi: 10.1371/journal.pbio.3002517. eCollection 2024 Feb.
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.
一群深度静止的、所谓的休眠造血干细胞（dHSCs）位于造血层级结构的顶端，作为造血干细胞的储备池。休眠状态可保护造血干细胞池在整个生命过程中不被耗尽；然而，过度休眠可能会妨碍对血液学应激的有效反应。尽管dHSCs具有重要意义，但其维持休眠的机制仍不清楚。在此，我们确定CD38是一种用于富集小鼠dHSCs的新型且广泛适用的表面标志物。我们证明，CD38环化酶活性的产物环磷酸腺苷二磷酸核糖（cADPR）通过增加内质网（ER）中Ca2+的释放来调节转录因子c-Fos的表达。随后，我们发现c-Fos诱导细胞周期抑制剂p57Kip2的表达以驱动造血干细胞休眠。此外，我们发现邻近的CD38阳性细胞处的CD38胞外酶活性可促进人类造血干细胞的静止。总之，CD38/cADPR/Ca2+/c-Fos/p57Kip2轴维持造血干细胞休眠。对该途径的药理学操作可为提高干细胞移植成功率以及损伤或疾病后血液再生提供新策略。
