title: Heparanase regulates retention and proliferation of primitive Sca-1+/c-Kit+/Lin- cells via modulation of the bone marrow microenvironment.
abstract: Heparanase is involved in tumor growth and metastasis. Because of its unique cleavage of heparan sulfate, which binds cytokines, chemokines and proteases, we hypothesized that heparanase is also involved in regulation of early stages of hematopoiesis. We report reduced numbers of maturing leukocytes but elevated levels of undifferentiated Sca-1(+)/c-Kit(+)/Lin(-) cells in the bone marrow (BM) of mice overexpressing heparanase (hpa-Tg). This resulted from increased proliferation and retention of the primitive cells in the BM microenvironment, manifested in increased SDF-1 turnover. Furthermore, heparanase overexpression in mice was accompanied by reduced protease activity of MMP-9, elastase, and cathepsin K, which regulate stem and progenitor cell mobilization. Moreover, increased retention of the progenitor cells also resulted from up-regulated levels of stem cell factor (SCF) in the BM, in particular in the stem cell-rich endosteum and endothelial regions. Increased SCF-induced adhesion of primitive Sca-1(+)/c-Kit(+)/Lin(-) cells to osteoblasts was also the result of elevation of the receptor c-Kit. Regulation of these phenomena is mediated by hyperphosphorylation of c-Myc in hematopoietic progenitors of hpa-Tg mice or after exogenous heparanase addition to wildtype BM cells in vitro. Altogether, our data suggest that heparanase modification of the BM microenvironment regulates the retention and proliferation of hematopoietic progenitor cells.
authors.affiliation: Department of Immunology, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Asaf
authors.initials: A
authors.lastname: Spiegel
authors.forename: Eyal
authors.initials: E
authors.lastname: Zcharia
authors.forename: Yaron
authors.initials: Y
authors.lastname: Vagima
authors.forename: Tomer
authors.initials: T
authors.lastname: Itkin
authors.forename: Alexander
authors.initials: A
authors.lastname: Kalinkovich
authors.forename: Ayelet
authors.initials: A
authors.lastname: Dar
authors.forename: Orit
authors.initials: O
authors.lastname: Kollet
authors.forename: Neta
authors.initials: N
authors.lastname: Netzer
authors.forename: Karin
authors.initials: K
authors.lastname: Golan
authors.forename: Itay
authors.initials: I
authors.lastname: Shafat
authors.forename: Neta
authors.initials: N
authors.lastname: Ilan
authors.forename: Arnon
authors.initials: A
authors.lastname: Nagler
authors.forename: Israel
authors.initials: I
authors.lastname: Vlodavsky
authors.forename: Tsvee
authors.initials: T
authors.lastname: Lapidot
mesh_terms: D000818:Animals; D001853:Bone Marrow; D001854:Bone Marrow Cells; D002448:Cell Adhesion; D002465:Cell Movement; D049109:Cell Proliferation; D054377:Chemokine CXCL12 / Q000378:metabolism; D005966:Glucuronidase / Q000502:physiology*; D006412:Hematopoietic Stem Cells / Q000166:cytology*; D016130:Immunophenotyping; D051379:Mice; D008822:Mice, Transgenic; D009363:Neoplasm Proteins; D010447:Peptide Hydrolases / Q000378:metabolism; D000099175:Heparanase
chemical_list: D054377:Chemokine CXCL12; D005966:Glucuronidase; D009363:Neoplasm Proteins; D010447:Peptide Hydrolases; D000099175:Heparanase; C515256:Cxcl12 protein, mouse