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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.
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Submitted October 2, 2007
Accepted February 28, 2008
Heparanase regulates retention and proliferation of primitive Sca-1+/c-Kit+/Lin- cells via modulation of the bone marrow microenvironment
Asaf Spiegel, Eyal Zcharia, Yaron Vagima, Tomer Itkin, Alexander Kalinkovich, Ayelet Dar, Orit Kollet, Neta Netzer, Karin Golan, Itay Shafat, Neta Ilan, Arnon Nagler, Israel Vlodavsky, and Tsvee Lapidot*
Department of Immunology, Weizmann Institute of Science, Rehovot, Israel
Department of Oncology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
Cancer and Vascular Biology Research Center, Rappaport Faculty of Medicine, Technion, Haifa, Israel
Department of Hematology & Bone Marrow Transplantation, Chaim Sheba Medical Center, Tel-Hashomer, Israel
* Corresponding author; email: tsvee.lapidot{at}weizmann.ac.il.
Heparanase is involved in tumor growth and metastasis. Due to its unique cleavage of heparan sulphate, which binds cytokines, chemokines and proteases, we hypothesized that this enzyme 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 over-expressing heparanase (hpa-Tg). This resulted from increased proliferation and retention of the primitive cells in the BM microenvironment, manifested in increased SDF-1 turnover. Additionally, heparanase over-expression 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 upregulated levels of 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 due to elevation of the receptor c-Kit. Regulation of these phenomena is mediated by hyper-phosphorylation of c-Myc in hematopoietic progenitor cells of hpa-Tg mice or following exogenous heparanase addition to wild-type BM cells in vitro. In all, our data suggest that heparanase modification of the BM microenvironment regulates the retention and proliferation of hematopoietic progenitor cells.
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