FGF-2 expands murine hematopoietic stem and progenitor cells via proliferation of stromal cells, c-Kit activation, and CXCL12 down-regulation.
Cytokine-induced expansion of hematopoietic stem and progenitor cells (HSPCs) is not fully understood. In the present study, we show that whereas steady-state hematopoiesis is normal in basic fibroblast growth factor (FGF-2)-knockout mice, parathyroid hormone stimulation and myeloablative treatments failed to induce normal HSPC proliferation and recovery. In vivo FGF-2 treatment expanded stromal cells, including perivascular Nestin(+) supportive stromal cells, which may facilitate HSPC expansion by increasing SCF and reducing CXCL12 via mir-31 up-regulation. FGF-2 predominantly expanded a heterogeneous population of undifferentiated HSPCs, preserving and increasing durable short- and long-term repopulation potential. Mechanistically, these effects were mediated by c-Kit receptor activation, STAT5 phosphorylation, and reduction of reactive oxygen species levels. Mice harboring defective c-Kit signaling exhibited abrogated HSPC expansion in response to FGF-2 treatment, which was accompanied by elevated reactive oxygen species levels. The results of the present study reveal a novel mechanism underlying FGF-2-mediated in vivo expansion of both HSPCs and their supportive stromal cells, which may be used to improve stem cell engraftment after clinical transplantation.
Department of Immunology, Weizmann Institute of Science, Rehovot, Israel.
Tomer
T
Itkin
Aya
A
Ludin
Ben
B
Gradus
Shiri
S
Gur-Cohen
Alexander
A
Kalinkovich
Amir
A
Schajnovitz
Yossi
Y
Ovadya
Orit
O
Kollet
Jonathan
J
Canaani
Elias
E
Shezen
Douglas J
DJ
Coffin
Grigori N
GN
Enikolopov
Thorsten
T
Berg
Wanda
W
Piacibello
Eran
E
Hornstein
Tsvee
T
Lapidot
D000818:Animals; D001483:Base Sequence; D016026:Bone Marrow Transplantation; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation; D002478:Cells, Cultured; D054377:Chemokine CXCL12 / Q000235:genetics / Q000378:metabolism*; D015536:Down-Regulation / Q000187:drug effects; D016222:Fibroblast Growth Factor 2 / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D005434:Flow Cytometry; D015870:Gene Expression / Q000187:drug effects; D006412:Hematopoietic Stem Cells / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008954:Models, Biological; D010281:Parathyroid Hormone / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050799:STAT5 Transcription Factor / Q000378:metabolism; D017154:Stromal Cells / Q000187:drug effects / Q000378:metabolism*
D054377:Chemokine CXCL12; D010281:Parathyroid Hormone; D017382:Reactive Oxygen Species; D050799:STAT5 Transcription Factor; D016222:Fibroblast Growth Factor 2; D019009:Proto-Oncogene Proteins c-kit