Herranz Óscar, Berrocal Pablo, Sicilia-Navarro Carmen, Fernández-Infante Cristina, Hernández-Cano Luis, Porras Almudena, Guerrero Carmen
Centro de Investigación del Cáncer (CIC), USAL-CSIC, Campus Unamuno S/N, Salamanca, Spain.
Instituto de Investigación Biomédica de Salamanca (IBSAL), Salamanca, Spain.
J Hematol Oncol. 2025 Apr 1;18(1):38. doi: 10.1186/s13045-025-01687-1.
C3G, a Rap1 GEF, promotes megakaryopoiesis and platelet function. Using transgenic and knock-out mouse models targeting C3G in megakaryocytes, we investigated whether C3G also affects the niche function of megakaryocytes during bone marrow (BM) recovery after myeloablation induced by 5-fluorouracil (5-FU), or total body irradiation (TBI) followed by bone marrow transplantation. C3G promoted megakaryocyte maturation and platelet production during recovery, along with increased white and red blood cell counts and enhanced survival of female mice after repeated doses of 5-FU. Additionally, megakaryocytes favored adipocyte differentiation through a C3G-mediated mechanism, likely involving Fgf1. Changes in the number or behavior of BM megakaryocytes and adipocytes influenced the hematopoietic stem cell pool, with C3G promoting its bias towards the myeloid-megakaryocytic lineage in both 5-FU- and TBI-ablated models. Therefore, C3G could be a potential target in therapies aimed at enhancing hematopoiesis in patients undergoing chemotherapy and/or BM transplantation.
C3G是一种Rap1鸟苷酸交换因子，可促进巨核细胞生成和血小板功能。我们使用针对巨核细胞中C3G的转基因和基因敲除小鼠模型，研究了C3G在5-氟尿嘧啶（5-FU）或全身照射（TBI）诱导的骨髓消融后，接着进行骨髓移植的骨髓（BM）恢复过程中，是否也会影响巨核细胞的微环境功能。在恢复过程中，C3G促进了巨核细胞成熟和血小板生成，同时在重复给予5-FU后，雌性小鼠的白细胞和红细胞计数增加，存活率提高。此外，巨核细胞通过一种可能涉及Fgf1的C3G介导机制，促进脂肪细胞分化。骨髓巨核细胞和脂肪细胞数量或行为的变化影响了造血干细胞库，在5-FU和TBI消融模型中，C3G均促进其向髓系-巨核细胞系倾斜。因此，C3G可能是旨在增强接受化疗和/或骨髓移植患者造血功能的治疗中的一个潜在靶点。
