FGF signaling facilitates postinjury recovery of mouse hematopoietic system.
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.
Stowers Institute for Medical Research, Kansas City, MO 64110, USA.
Meng
M
Zhao
Jason T
JT
Ross
Tomer
T
Itkin
John M
JM
Perry
Aparna
A
Venkatraman
Jeffrey S
JS
Haug
Mark J
MJ
Hembree
Chu-Xia
CX
Deng
Tsvee
T
Lapidot
Xi C
XC
He
Linheng
L
Li
D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D001854:Bone Marrow Cells / Q000187:drug effects / Q000378:metabolism; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation; D002478:Cells, Cultured; D005260:Female; D005346:Fibroblast Growth Factors / Q000378:metabolism*; D005434:Flow Cytometry; D005472:Fluorouracil / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects; D006413:Hematopoietic System / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D007150:Immunohistochemistry; D008297:Male; D008533:Megakaryocytes / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000378:metabolism; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000235:genetics / Q000378:metabolism*; D019718:Receptors, CXCR4 / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction
D000964:Antimetabolites, Antineoplastic; C514936:CXCR4 protein, mouse; D016328:NF-kappa B; D019718:Receptors, CXCR4; D005346:Fibroblast Growth Factors; C496349:Fgfr1 protein, mouse; D051496:Receptor, Fibroblast Growth Factor, Type 1; D005472:Fluorouracil