Src family kinase-mediated negative regulation of hematopoietic stem cell mobilization involves both intrinsic and microenvironmental factors.
OBJECTIVE
The intracellular signals that contribute to granulocyte colony-stimulating factor (G-CSF) receptor induced stem cell mobilization are poorly characterized.


METHODS
We show enhanced G-CSF induced mobilization of stem cells in mice deficient in expression of Src family kinases (SFK-/-), which is associated with hypersensitivity of SFK-/- bone marrow cells to G-CSF as well as sustained activation of signal transducer and activator of transcription-3.


RESULTS
A proteome map of the bone marrow fluid derived from wild-type and SFK-/- mice revealed a significant global reduction in the number of proteins in SFK-/- mice compared to controls, which was associated with elevated matrix metalloproteinase-9 levels, reduced stromal-derived factor-1 expression, and enhanced breakdown of vascular cell adhesion molecule-1. Transplantation of wild-type or SFK-/- stem cells into wild-type mice and treatment with G-CSF recapitulated the G-CSF-induced increase in stem cell mobilization noted in SFK-/- nontransplanted mice; however, the increase was significantly less. G-CSF treatment of SFK-/- mice engrafted with wild-type stem cells also demonstrated a modest increase in stem cell mobilization compared to controls, however, the observed increase was greatest in mice completely devoid of SFKs.


CONCLUSIONS
These data suggest an involvement of both hematopoietic intrinsic and microenvironmental factors in Src kinase-mediated mobilization of stem cells and identify Src kinases as potential targets for modulating stem cell mobilization.
Borneo
Jovencio
J
Department of Pediatrics, Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
Munugalavadla
Veerendra
V
Sims
Emily C
EC
Vemula
Sasidhar
S
Orschell
Christie M
CM
Yoder
Merv
M
Kapur
Reuben
R
D000818:Animals; D002465:Cell Movement; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000502:physiology; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology; D019650:Hematopoietic Stem Cell Mobilization; D020781:Matrix Metalloproteinase 1 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D054380:Receptors, CXCR5; D019707:Receptors, Chemokine / Q000502:physiology; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism; D019061:src-Family Kinases / Q000502:physiology*
C513179:CXCR5 protein, mouse; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; C515256:Cxcl12 protein, mouse; D054380:Receptors, CXCR5; D019707:Receptors, Chemokine; D019010:Vascular Cell Adhesion Molecule-1; D016179:Granulocyte Colony-Stimulating Factor; D019061:src-Family Kinases; D020781:Matrix Metalloproteinase 1