MT1-MMP and RECK are involved in human CD34+ progenitor cell retention, egress, and mobilization
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
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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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 6

MT1-MMP and RECK activity oppositely affects human and murine HPC egress.

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MT1-MMP and RECK activity oppositely affects human and murine HPC egress...
(A) NOD/SCID chimeric mice were treated with G-CSF for 5 consecutive days. Anti–MT1-MMP or anti-VLA6 Abs were injected i.p. 20 μg/mouse on days 3–5 of G-CSF administration. Numbers of human CD45+, CD34+, and CD34+/38–/low cells in the PB were determined by flow cytometry and normalized as described in Methods. Data are presented as mean ± SD of 3–5 independent experiments, 3–4 mice per group. *P < 0.05. (B) Chimeric B6.SJL (CD45.1+) mice, previously transplanted with 2 × 105 BM cells derived from MT1-MMP KO mice or WT littermates (CD45.2+) were treated with G-CSF for 3 consecutive days. Numbers of donor-derived c-kit+CD45.2+ in the PB were determined by flow cytometry and normalized as described in Methods. Data are represented as fold change compared with sham-injected mice. Mean ± SEM of 4 independent experiments, n = 2–3 mice per group. *P < 0.05. (C) NOD/SCID chimeric mice were injected i.p. with 20 μg/mouse of anti-RECK or IgG control Abs for 2 consecutive days. The number of CD45+ and CD34+ human cells per ml PB was determined 14–16 hours after last injection and expressed as mean ± SD of at least 3 independent experiments, 2 mice per treatment. *P < 0.05. No significant changes were detected in IgG-treated as compared with sham-injected mice. (D) Representative gelatin zymography and densitometry analysis (mean ± SD) of MMP-2 and MMP-9 levels in the BM supernatants from sham-injected (–) or anti-RECK–injected (+) mice are shown. **P < 0.01.