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 2

MT1-MMP and RECK expression are inversely regulated by G-CSF.

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MT1-MMP and RECK expression are inversely regulated by G-CSF. (A) Real-t...
(A) Real-time PCR analysis of human MT1-MMP and RECK expression in the BM cells of sham-injected (–) or G-CSF–treated (+) chimeric mice. mRNA levels upon G-CSF treatment are shown as fold change relative to sham-injected mice (mean ± SD of 4 independent experiments, as normalized to human GAPDH control). **P < 0.01. (B) Representative immunohistochemical analysis of MT1-MMP and RECK expression (brown staining) in BM section of highly engrafted G-CSF–treated or sham-injected control chimeric mice. Scale bar: 50 μm. (C) Relative MT1-MMP activity determined in crude plasma membrane extracts from the BM cells of sham-injected (control) or G-CSF–treated mice. Measurements of fluorogenic substrate cleavage (in arbitrary units) as a function of incubation time with MT1-MMP–containing extracts are shown as mean ± SD of 3 independent experiments with 2 mice per treatment. *P < 0.05 between the treatments. (D and E) MT1-MMP and RECK expression on CD45+, CD34+, and CD34+/CD38-/low human cells detected in the BM and PB of sham-injected or G-CSF–treated chimeric mice. Flow cytometry analysis data are represented as fold change in MFI relative to human BM cells from sham-injected mice (mean ± SD of 6 independent experiments, 2 mice per treatment). **P < 0.01.