Recruitment of stem and progenitor cells from the bone marrow niche requires MMP-9 mediated release of kit-ligand.
Stem cells within the bone marrow (BM) exist in a quiescent state or are instructed to differentiate and mobilize to circulation following specific signals. Matrix metalloproteinase-9 (MMP-9), induced in BM cells, releases soluble Kit-ligand (sKitL), permitting the transfer of endothelial and hematopoietic stem cells (HSCs) from the quiescent to proliferative niche. BM ablation induces SDF-1, which upregulates MMP-9 expression, and causes shedding of sKitL and recruitment of c-Kit+ stem/progenitors. In MMP-9-/- mice, release of sKitL and HSC motility are impaired, resulting in failure of hematopoietic recovery and increased mortality, while exogenous sKitL restores hematopoiesis and survival after BM ablation. Release of sKitL by MMP-9 enables BM repopulating cells to translocate to a permissive vascular niche favoring differentiation and reconstitution of the stem/progenitor cell pool.
Heissig
Beate
B
Division of Hematology-Oncology, Cornell University Medical College, New York, NY 10021, USA.
Hattori
Koichi
K
Dias
Sergio
S
Friedrich
Matthias
M
Ferris
Barbara
B
Hackett
Neil R
NR
Crystal
Ronald G
RG
Besmer
Peter
P
Lyden
David
D
Moore
Malcolm A S
MA
Werb
Zena
Z
Rafii
Shahin
S
D000818:Animals; D001853:Bone Marrow / Q000187:drug effects / Q000201:enzymology*; D002454:Cell Differentiation / Q000502:physiology*; D002465:Cell Movement / Q000502:physiology*; D002478:Cells, Cultured; D054377:Chemokine CXCL12; D018925:Chemokines / Q000494:pharmacology; D019743:Chemokines, CXC / Q000494:pharmacology; D016228:Endothelial Growth Factors / Q000494:pharmacology; D005260:Female; D005472:Fluorouracil / Q000494:pharmacology; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000378:metabolism*; D007166:Immunosuppressive Agents / Q000494:pharmacology; D008222:Lymphokines / Q000494:pharmacology; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000172:deficiency* / Q000235:genetics; D008533:Megakaryocytes / Q000187:drug effects / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D016513:Mice, SCID; D022423:Myeloid Cells / Q000187:drug effects / Q000276:immunology; D020127:Recovery of Function / Q000187:drug effects / Q000276:immunology; D019089:Stem Cell Factor / Q000378:metabolism* / Q000494:pharmacology; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D054377:Chemokine CXCL12; D018925:Chemokines; D019743:Chemokines, CXC; C515256:Cxcl12 protein, mouse; D016228:Endothelial Growth Factors; D007166:Immunosuppressive Agents; D008222:Lymphokines; D019089:Stem Cell Factor; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D020780:Matrix Metalloproteinase 9; D005472:Fluorouracil