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 March 2, 2009; First 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 1

MT1-MMP expression positively correlates with egress and G-CSF mobilization of human CD34+ progenitors.

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MT1-MMP expression positively correlates with egress and G-CSF mobilizat...
(A) Left: Representative flow cytometry analysis of membranal MT1-MMP and RECK expression on CD34+ cells enriched from the untreated (steady state) BM or PB, or PB of G-CSF–mobilized healthy human donors (MPB). Dotted lines indicate background labeling with secondary IgG. Numbers denote MFI values of MT1-MMP and RECK immunolabeling (mean ± SD of 3–6 independent experiments). Right: Representative flow cytometry analysis of MT1-MMP and RECK co-expression on human steady-state BM CD34+ progenitors. (B) G-CSF treatment ex vivo increases MT1-MMP expression on steady-state BM CD34+ cells. Flow cytometry analysis of MT1-MMP levels on CD34+ cells enriched from the BM of healthy donors (n = 6) and cultured for 48 hours in the presence of 100 ng/ml G-CSF, IL-6, SDF-1, or SCF or left untreated (–). Results are shown as fold change in MFI relative to untreated (mean ± SD; *P < 0.05). (C and D) Membranal MT1-MMP expression on MPB human CD34+ HPCs. Linear regression analysis (solid lines) and 95% confidence interval (dotted lines) are shown. (C) CD34+ cells were enriched from the PB of 21 consecutive G-CSF–treated healthy donors and immediately immunolabeled for MT1-MMP. (D) 29 consecutive patients were treated with chemotherapy and G-CSF, as described in Methods. PB cells were isolated on the first collection day and co-immunolabeled with anti–MT1-MMP, anti-CD34, and anti-CD45 Abs.