Department of Immunology, Weizmann Institute of Science, Rehovot, Israel.
Curr Opin Hematol. 2013 May;20(3):237-44. doi: 10.1097/MOH.0b013e3283606162.
Fibroblast growth factor (FGF) signaling activates many bone marrow cell types, including various stem cells, osteoblasts, and osteoclasts. However, the role of FGF signaling in regulation of normal and leukemic stem cells is poorly understood. This review highlights the physiological roles of FGF signaling in regulating bone marrow mesenchymal and hematopoietic stem and progenitor cells (MSPCs and HSPCs) and their dynamic microenvironment. In addition, this review summarizes the recent studies which provide an overview of FGF-activated mechanisms regulating physiological stem cell maintenance, self-renewal, and motility.
Current results indicate that partial deficiencies in FGF signaling lead to mild defects in hematopoiesis and bone remodeling. However, FGF signaling was shown to be crucial for stem cell self-renewal and for proper hematopoietic poststress recovery. FGF signaling activation was shown to be important also for rapid AMD3100 or post 5-fluorouracil-induced HSPC mobilization. In vivo, FGF-2 administration successfully expanded both MSPCs and HSPCs. FGF-induced expansion was characterized by enhanced HSPC cycling without further exhaustion of the stem cell pool. In addition, FGF signaling expands and remodels the supportive MSPC niche cells. Finally, FGF signaling is constitutively activated in many leukemias, suggesting that malignant HSPCs exploit this pathway for their constant expansion and for remodeling a malignant-supportive microenvironment.
The summarized studies, concerning regulation of stem cells and their microenvironment, suggest that FGF signaling manipulation can serve to improve current clinical stem cell mobilization and transplantation protocols. In addition, it may help to develop therapies specifically targeting leukemic stem cells and their supportive microenvironment.
成纤维细胞生长因子 (FGF) 信号激活多种骨髓细胞类型，包括各种干细胞、成骨细胞和破骨细胞。然而，FGF 信号在调节正常和白血病干细胞中的作用知之甚少。本综述强调了 FGF 信号在调节骨髓间充质和造血干细胞和祖细胞 (MSPCs 和 HSPCs) 及其动态微环境中的生理作用。此外，本综述总结了最近的研究，这些研究概述了 FGF 激活机制在调节生理干细胞维持、自我更新和运动中的作用。
目前的结果表明，FGF 信号的部分缺陷导致造血和骨重塑的轻微缺陷。然而，FGF 信号对于干细胞自我更新和适当的造血应激后恢复至关重要。FGF 信号的激活对于 AMD3100 或 5-氟尿嘧啶诱导后的 HSPC 动员的快速发生也很重要。在体内，FGF-2 给药成功地扩增了 MSPC 和 HSPC。FGF 诱导的扩增表现为 HSPC 循环增强，而不会进一步耗尽干细胞池。此外，FGF 信号扩增和重塑支持性 MSPC 龛细胞。最后，许多白血病中持续激活 FGF 信号，表明恶性 HSPC 利用该途径进行持续扩增和重塑恶性支持性微环境。
关于干细胞及其微环境的调节的综述研究表明，FGF 信号的操纵可以用于改善当前的临床干细胞动员和移植方案。此外，它可能有助于开发专门针对白血病干细胞及其支持性微环境的治疗方法。
