Hematopoietic stem cell maintenance by Mediator transcriptional coregulator complex

在缺乏介体转录辅助调节复合体MED1亚单位的小鼠胚胎成纤维细胞(MEF)中，FGF7的表达减弱。当正常小鼠骨髓(BM)细胞与BM基质细胞在抗Fgf7抗体存在下共同培养时，BM细胞的生长和长时间培养启动细胞(LTC-ICs)的数量显著减少。抗Fgf7抗体还可抑制MB1基质细胞依赖的髓母细胞瘤细胞的增殖和鹅卵石形成。在BM细胞与MED_1-/-MEF共培养中加入重组Fgf7可增加BM细胞和LTC-IC的数量。BM细胞表达FGFF7及其同源受体FGFR2IIIb，而MEF和BM基质细胞均表达FGFF7和FGFR2IIIb。FGF7激活野生型MEF、MED1基因敲除型MEF和骨髓基质细胞中FGFR2IIIb的下游靶点。综上所述，我们认为Fgf7通过表达在基质细胞上的FGFR2IIIb间接支持HSPC和白血病启动细胞。

FGF7 expression was attenuated in mouse embryonic fibroblasts (MEFs) deficient for the MED1 subunit of the Mediator transcriptional coregulator complex. When normal mouse bone marrow (BM) cells were cocultured with BM stromal cells in the presence of anti-FGF7 antibody, the growth of BM cells and the number of long-time culture-initiating cells (LTC-ICs) decreased significantly. Anti-FGF7 antibody also attenuated the proliferation and cobblestone formation of MB1 stromal cell-dependent myeloblastoma cells. The addition of recombinant FGF7 to the coculture of BM cells and Med1-/- MEFs increased BM cells and LTC-ICs. FGF7 and its cognate receptor, FGFR2IIIb, were undetectable in BM cells, but MEFs and BM stromal cells expressed both. FGF7 activated downstream targets of FGFR2IIIb in wild type MEFs, MED1 knockout MEFs, and BM stromal cells. Taken together, we propose that FGF7 supports HSPCs and leukemia-initiating cells indirectly via FGFR2IIIb expressed on stromal cells.