MT1-MMP and RECK are involved in human CD34+ progenitor cell retention, egress, and mobilization
| Autor: | Ester Rosenthal, Tsvee Lapidot, Shoham Shivtiel, Karin Golan, Orit Kollet, Abraham Avigdor, Polina Goichberg, David Naor, Arnon Nagler, Isabelle Petit, Alexander Kalinkovich, Ayelet Dar, Igor B. Resnick, Orly Perl, Melania Tesio, Yaron Vagima, Yechiel N. Gellman, Izhar Hardan |
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| Jazyk: | angličtina |
| Rok vydání: | 2009 |
| Předmět: |
CD34
Antigens CD34 Bone Marrow Cells Mice SCID GPI-Linked Proteins Gene Expression Regulation Enzymologic Mice Antigens CD Cell Movement Mice Inbred NOD Granulocyte Colony-Stimulating Factor Matrix Metalloproteinase 14 Animals Humans RNA Messenger Progenitor cell RNA Small Interfering Cell adhesion Hematopoietic Stem Cell Mobilization Mice Knockout Membrane Glycoproteins biology Chimera Chemotaxis CD44 General Medicine Hematopoietic Stem Cells Molecular biology Cell biology Gene Expression Regulation Neoplastic Haematopoiesis biology.protein Homing (hematopoietic) Research Article |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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