Stowers Institute for Medical Research, Kansas City, MO 64110, USA.
Blood. 2012 Aug 30;120(9):1831-42. doi: 10.1182/blood-2011-11-393991. Epub 2012 Jul 16.
Previous studies have shown that fibroblast growth factor (FGF) signaling promotes hematopoietic stem and progenitor cell (HSPC) expansion in vitro. However, it is unknown whether FGF promotes HSPC expansion in vivo. Here we examined FGF receptor 1 (FGFR1) expression and investigated its in vivo function in HSPCs. Conditional knockout (CKO) of Fgfr1 did not affect phenotypical number of HSPCs and homeostatic hematopoiesis, but led to a reduced engraftment only in the secondary transplantation. When treated with 5-fluorouracil (5FU), the Fgfr1 CKO mice showed defects in both proliferation and subsequent mobilization of HSPCs. We identified megakaryocytes (Mks) as a major resource for FGF production, and further discovered a novel mechanism by which Mks underwent FGF-FGFR signaling dependent expansion to accelerate rapid FGF production under stress. Within HSPCs, we observed an up-regulation of nuclear factor κB and CXCR4, a receptor for the chemoattractant SDF-1, in response to bone marrow damage only in control but not in Fgfr1 CKO model, accounting for the corresponding defects in proliferation and migration of HSPCs. This study provides the first in vivo evidence that FGF signaling facilitates postinjury recovery of the mouse hematopoietic system by promoting proliferation and facilitating mobilization of HSPCs.
先前的研究表明，成纤维细胞生长因子 (FGF) 信号在体外促进造血干细胞和祖细胞 (HSPC) 的扩增。然而，FGF 是否在体内促进 HSPC 扩增尚不清楚。在这里，我们检查了 FGF 受体 1 (FGFR1) 的表达，并研究了其在 HSPC 中的体内功能。FGFR1 的条件敲除 (CKO) 并不影响 HSPC 的表型数量和稳态造血，但仅在二次移植中导致植入减少。当用 5-氟尿嘧啶 (5FU) 处理时，Fgfr1 CKO 小鼠在 HSPC 的增殖和随后的动员中均存在缺陷。我们确定巨核细胞 (Mks) 是 FGF 产生的主要来源，并进一步发现了一种新的机制，即 Mks 通过 FGF-FGFR 信号依赖性扩增来加速应激下快速的 FGF 产生。在 HSPC 内，我们仅在对照模型中观察到 NF-κB 和趋化因子 SDF-1 的受体 CXCR4 的核因子上调，而在 Fgfr1 CKO 模型中则没有，这解释了 HSPC 增殖和迁移的相应缺陷。这项研究提供了第一个体内证据，表明 FGF 信号通过促进 HSPC 的增殖和动员来促进小鼠造血系统损伤后的恢复。
