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 5

Functional MT1-MMP is involved in BM homing and engraftment of HPCs.

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Functional MT1-MMP is involved in BM homing and engraftment of HPCs. (A ...
(A and B) Enriched human MPB CD34+ cells were pre-incubated or not with anti–MT1-MMP or control anti-VLA6 Abs (A) or transfected with either control siRNA or MT1-MMP siRNA (B), as in Figure 4B, and transplanted into sub-lethally irradiated NOD/SCID mice. Results are shown as numbers of human cells per 106 total cells detected in the BM of recipient mice. (A) Mean ± SD of 3–5 independent experiments, at least 3 mice per treatment. *P < 0.05. (B) Mean ± SD of 3 independent experiments, 2 mice per treatment, relative to control siRNA. *P < 0.05. Representative flow cytometry analysis of BM homing of human CD45+/CD34+ cells (numbers are indicated) is shown on the right. (C) Mouse BM cells were obtained from the WT (Mt1-mmp+/+) and MT1-MMP KO (Mt1-mmp–/–) littermates. Data are expressed as numbers of CFSE+ donor cells per 106 total cells detected in the BM of transplanted NOD/SCID mice (mean ± SD of 3 independent experiments, 2 mice per treatment). **P = 0.02. Representative flow cytometry analysis is shown on the right, numbers indicate CFSE+ donor cells per 106 total cells detected in the BM. (D) BM cells obtained from MT1-MMP KO or WT mice (CD45.2+) were transplanted at the indicated cell doses (5 × 104 white circles and 2 × 105 black circles) into sub-lethally irradiated B6.SJL (CD45.1+) recipients. Results are shown as percentage of donor-derived c-kit+CD45.2+ cells detected in the BM of recipients (CD45.1+ mice). Mean ± SD of 4 independent experiments. **P < 0.01. Average values for each group are indicated by horizontal lines.