title: Release of matrix metalloproteinase-8 during physiological trafficking and induced mobilization of human hematopoietic stem cells.
abstract: Previous studies indicate that the release of proteases, including the gelatinase matrix metalloproteinase (MMP)-9, from mature granulocytes plays a crucial role in cytokine-induced hematopoietic stem and progenitor cell (HSPC) mobilization. However, studies with MMP-9-deficient mice revealed that HSPC mobilization was normal in these animals, suggesting that additional proteases must be active at clinically relevant cytokine concentrations. In the present study, we provide evidence that the collagenase MMP-8 is involved in stem cell mobilization. A rapid release of MMP-8 from isolated neutrophil granulocytes can be observed during an in vitro culture. During granulocyte colony-stimulating factor-induced HSPC mobilization, highly elevated serum concentrations of MMP-8 were observed on days 4 to 6 of the mobilization regimen, concomitantly with elevated MMP-9 serum levels and higher numbers of circulating CD34(+) cells. Elevated serum concentrations of both proteases were also found in umbilical cord blood serum. In functional assays, adhesion of HSPC to osteoblasts as an essential component of the endosteal stem cell niche is negatively influenced by MMP-8. The chemokine CXCL12, which is critically involved in stem cell trafficking, can be proteolytically processed by MMP-8 treatment. This degradation has a strong inhibitory influence on HSPC migration. Taken together, our data strongly suggest that MMP-8 can be directly involved in hematopoietic stem cell mobilization and trafficking.
authors.affiliation: Section for Transplantation Immunology and Immunohematology, University Medical Clinic, Center for Medical Research, University of Tübingen, Tübingen, Germany.
authors.forename: Carolin
authors.initials: C
authors.lastname: Steinl
authors.forename: Mike
authors.initials: M
authors.lastname: Essl
authors.forename: Thomas D
authors.initials: TD
authors.lastname: Schreiber
authors.forename: Konstanze
authors.initials: K
authors.lastname: Geiger
authors.forename: Lea
authors.initials: L
authors.lastname: Prokop
authors.forename: Stefan
authors.initials: S
authors.lastname: Stevanović
authors.forename: Oliver
authors.initials: O
authors.lastname: Pötz
authors.forename: Harald
authors.initials: H
authors.lastname: Abele
authors.forename: Johannes T
authors.initials: JT
authors.lastname: Wessels
authors.forename: Wilhelm K
authors.initials: WK
authors.lastname: Aicher
authors.forename: Gerd
authors.initials: G
authors.lastname: Klein
mesh_terms: D000293:Adolescent; D000328:Adult; D001853:Bone Marrow / Q000201:enzymology; D002448:Cell Adhesion; D002465:Cell Movement; D002478:Cells, Cultured; D054377:Chemokine CXCL12 / Q000502:physiology; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D005312:Fetal Blood / Q000201:enzymology; D016179:Granulocyte Colony-Stimulating Factor / Q000502:physiology; D019650:Hematopoietic Stem Cell Mobilization; D006412:Hematopoietic Stem Cells / Q000201:enzymology*; D006801:Humans; D020784:Matrix Metalloproteinase 8 / Q000097:blood* / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D009504:Neutrophils / Q000201:enzymology; D021381:Protein Transport; D059748:Proteolysis; D055815:Young Adult
chemical_list: C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; D016326:Extracellular Matrix Proteins; D016179:Granulocyte Colony-Stimulating Factor; C488762:MMP8 protein, human; D020784:Matrix Metalloproteinase 8; C579270:MMP9 protein, human; D020780:Matrix Metalloproteinase 9