MT1-MMP and RECK are involved in human CD34+ progenitor cell retention, egress, and mobilization

• Published in: The Journal of clinical investigation Vol. 119; no. 3; pp. 492 - 503
• Main Authors: Vagima, Yaron, Avigdor, Abraham, Goichberg, Polina, Shivtiel, Shoham, Tesio, Melania, Kalinkovich, Alexander, Golan, Karin, Dar, Ayelet, Kollet, Orit, Petit, Isabelle, Perl, Orly, Rosenthal, Ester, Resnick, Igor, Hardan, Izhar, Gellman, Yechiel N, Naor, David, Nagler, Arnon, Lapidot, Tsvee
• Format: Journal Article
• Language: English
• Published: United States American Society for Clinical Investigation 02.03.2009
• Subjects: Animals; Antigens, CD - analysis; Antigens, CD34 - analysis; Bone Marrow Cells - physiology; Cell Movement - physiology; Chemotaxis; Chimera - genetics; Gene Expression Regulation, Enzymologic - drug effects; Gene Expression Regulation, Neoplastic - drug effects; GPI-Linked Proteins; Granulocyte Colony-Stimulating Factor - pharmacology; Hematopoietic Stem Cell Mobilization; Hematopoietic Stem Cells - drug effects; Hematopoietic Stem Cells - immunology; Hematopoietic Stem Cells - physiology; Humans; Matrix Metalloproteinase 14 - deficiency; Matrix Metalloproteinase 14 - drug effects; Matrix Metalloproteinase 14 - genetics; Matrix Metalloproteinase 14 - metabolism; Membrane Glycoproteins - drug effects; Membrane Glycoproteins - genetics; Membrane Glycoproteins - metabolism; Mice; Mice, Inbred NOD; Mice, Knockout; Mice, SCID; RNA, Messenger - genetics; RNA, Small Interfering - genetics
• ISSN: 0021-9738; 1558-8238
• DOI: 10.1172/jci36541

The mechanisms governing hematopoietic progenitor cell mobilization are not fully understood. We report higher membrane type 1-MMP (MT1-MMP) and lower expression of the MT1-MMP inhibitor, reversion-inducing cysteine-rich protein with Kazal motifs (RECK), on isolated circulating human CD34+ progenitor cells compared with immature BM cells. The expression of MT1-MMP correlated with clinical mobilization of CD34+ cells in healthy donors and patients with lymphoid malignancies. Treatment with G-CSF further increased MT1-MMP and decreased RECK expression in human and murine hematopoietic cells in a PI3K/Akt-dependent manner, resulting in elevated MT1-MMP activity. Blocking MT1-MMP function by Abs or siRNAs impaired chemotaxis and homing of G-CSF-mobilized human CD34+ progenitors. The mobilization of immature and maturing human progenitors in chimeric NOD/SCID mice by G-CSF was inhibited by anti-MT1-MMP treatment, while RECK neutralization promoted motility and egress of BM CD34+ cells. BM c-kit+ cells from MT1-MMP-deficient mice also exhibited inferior chemotaxis, reduced homing and engraftment capacities, and impaired G-CSF-induced mobilization in murine chimeras. Membranal CD44 cleavage by MT1-MMP was enhanced following G-CSF treatment, reducing CD34+ cell adhesion. Accordingly, CD44-deficient mice had a higher frequency of circulating progenitors. Our results reveal that the motility, adhesion, homing, and mobilization of human hematopoietic progenitor cells are regulated in a cell-autonomous manner by dynamic and opposite changes in MT1-MMP and RECK expression.