MT1-MMP and RECK are involved in human CD34+ progenitor cell retention, egress, and mobilization
Yaron Vagima, … , Arnon Nagler, Tsvee Lapidot
Yaron Vagima, … , Arnon Nagler, Tsvee Lapidot
Published February 9, 2009
Citation Information: J Clin Invest. 2009;119(3):492-503. https://doi.org/10.1172/JCI36541.
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Research Article Hematology

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

Abstract

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.

Authors

Yaron Vagima, Abraham Avigdor, Polina Goichberg, Shoham Shivtiel, Melania Tesio, Alexander Kalinkovich, Karin Golan, Ayelet Dar, Orit Kollet, Isabelle Petit, Orly Perl, Ester Rosenthal, Igor Resnick, Izhar Hardan, Yechiel N. Gellman, David Naor, Arnon Nagler, Tsvee Lapidot

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Figure 4

MT1-MMP and RECK oppositely affect in vitro motility of human and murine HPCs.

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MT1-MMP and RECK oppositely affect in vitro motility of human and murine...
(A) Enriched human MPB CD34+ cells were treated with anti–MT1-MMP Abs, TIMP-2, or rabbit serum (control IgG). Enriched human BM CD34+ cells were treated with anti-RECK Abs (αRECK) or IgG1 (control IgG). Cells were allowed to migrate via Matrigel. Data are shown as percentage of migrating cells from the input cell number (mean ± SD of 3 independent experiments in triplicates). *P < 0.05, **P < 0.01. (B) Enriched human MPB CD34+ cells were transfected with control (siCTRL) or MT1-MMP (siMT1) siRNA. Data are shown as described in A (mean ± SD of 3 independent experiments in duplicates). *P < 0.05. Representative flow cytometry analysis of MT1-MMP expression in siCTRL and siMT1 transfected cells is shown. (C) BM mononuclear cells were obtained form G-CSF– or sham-injected chimeric mice (control) and treated with αMT1-MMP or TIMP-2. Following trans-Matrigel migration, numbers of human CD34+/CD38–/low were determined by flow cytometry. Data are expressed as percentage change compared with migration of untreated cells from G-CSF–mobilized chimeric mice (set at 100%) (mean ± SD, 4 independent experiments performed in triplicate). *P < 0.05, **P < 0.01. (D) BM mononuclear cells were obtained from chimeric B6.SJL (CD45.1+) mice treated for 3 days with G-CSF and previously transplanted with CD45.2+ BM cells from MT1-MMP KO (Mt1-mmp–/–) mice or WT littermates (Mt1-mmp+/+) and allowed to migrate to SDF-1 via Matrigel-coated filters. Data are expressed as percentage of migrating CD45.2+c-kit+ cells from the input cell number as determined by flow cytometry (mean ± SD, 3 independent experiments performed in quadruplicate). **P < 0.01.