SEARCH:   Advanced

Blood, 15 May 2008, Vol. 111, No. 10, pp. 4934-4943. Prepublished online as a Blood First Edition Paper on March 11, 2008; DOI 10.1182/blood-2007-10-116145. This Article Full Text Full Text (PDF) All Versions of this Article: blood-2007-10-116145v1 111/10/4934    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Google Scholar Articles by Spiegel, A. Articles by Lapidot, T. PubMed PubMed Citation Articles by Spiegel, A. Articles by Lapidot, T. Related Collections Hematopoiesis Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  HEMATOPOIESIS AND STEM CELLS Heparanase regulates retention and proliferation of primitive Sca-1+/c-Kit+/Lin– cells via modulation of the bone marrow microenvironment Asaf Spiegel1, Eyal Zcharia2, Yaron Vagima1, Tomer Itkin1, Alexander Kalinkovich1, Ayelet Dar1, Orit Kollet1, Neta Netzer1, Karin Golan1, Itay Shafat3, Neta Ilan3, Arnon Nagler4, Israel Vlodavsky3, and Tsvee Lapidot1 1 Department of Immunology, Weizmann Institute of Science, Rehovot; 2 Department of Oncology, Hadassah-Hebrew University Medical Center, Jerusalem; 3 Cancer and Vascular Biology Research Center, Rappaport Faculty of Medicine, Technion, Haifa; and 4 Department of Hematology & Bone Marrow Transplantation, Chaim Sheba Medical Center, Tel-Hashomer, Israel 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. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

	Blood Online is supported in part by Genentech BioOncology and Biogen Idec
	Copyright © 2008 by American Society of Hematology         Online ISSN: 1528-0020