FGF7 supports hematopoietic stem and progenitor cells and niche-dependent myeloblastoma cells via autocrine action on bone marrow stromal cells in vitro

Abstract

FGF1 and FGF2 support hematopoietic stem and progenitor cells (HSPCs) under stress conditions. In this study, we show that fibroblast growth factor (FGF7) may be a novel niche factor for HSPC support and leukemic growth. 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 Med1(+/+) MEFs or 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 Med1(+/+) and Med1(-/-) MEFs and BM stromal cells. Taken together, we propose that FGF7 supports HSPCs and leukemia-initiating cells indirectly via FGFR2IIIb expressed on stromal cells.

Periostin supports hematopoietic progenitor cells and niche-dependent myeloblastoma cells in vitro

“…We have previously reported that the Med1 −/− MEFs have reduced ability to promote growth of BM cells and to support of HPCs in vitro , at least partly, through the reduced production of full-length osteopontin [8] and FGF7 [9]. Comparative microarray analysis of the Med1 +/+ p53 −/− and Med1 −/− p53 −/− MEFs has revealed that Postn expression is also attenuated in Med1 −/− MEFs (GEO accession number GSE22471) [8].…”

“…Cells were trypsinized, harvested and cultured in complete methylcellulose medium (MethoCult M3434; Stem Cell Technologies) for all types of colonies at 37 °C for 14 days, and the colonies were counted [8,9]. …”

“…DNA synthesis of cocultured hematopoietic cells in 24-well plates was measured by bromodeoxyuridine (BrdU) incorporation as described [8,9]. …”

“…We previously reported that Med1 −/− mouse embryonic fibroblasts (MEFs) have an attenuated ability to support hematopoietic progenitor cells (HPCs) relative wild-type MEFs, and that the attenuated expression of full-length osteopontin or FGF7 in Med1 −/− MEFs is responsible for the observed phenotype. Thus, osteopontin and FGF7, produced by BM mesenchymal stromal cells, have been identified as important niche factors [8,9]. …”

Integrated bioinformatic analysis of microarray data reveals shared gene signature between MDS and AML

“…In the DEGs of our meta-analysis, FGF7 and FGFR3 gene expression were both upregulated. FGF7 is a ligand of FGFR2b with high affinity, which have been recently reported to serve as a potentially niche factor for hematopoietic stem and progenitor cells (HSPCs) support and leukemic growth by activating FGFR2b signaling pathway (51). Besides, the truncated recombinant human FGF7, palifermin, which compete for binding of FGFR2b, has been FDA-approved for the treatment of patients with oral mucositis (52).…”