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

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.sup.+] pr...

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Published in:The Journal of clinical investigation 2009-03, Vol.119 (3), p.492
Main Authors: Vagima, Yaron, Avigdor, Abraham, Goichberg, Polina, Shivtiel, Shoham, Tesio, Melania, Kalinkovich, Alexander, Golan, Karin, Dar, Ayelet, Kollet, Orit, Petit, Isabelle, Perl, Orly, Rosenthal, Ester, Resnick, Igor, Hardan, Izhar, Gellman, Yechiel N, Naor, David, Nagler, Arnon, Lapidot, Tsvee
Format: Article
Language:English
Subjects:
Cell migration
Genetic aspects
Hematopoietic stem cells
Metalloenzymes
Physiological aspects
Online Access:Get full text
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Summary: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.sup.+] progenitor cells compared with immature BM cells. The expression of MT1-MMP correlated with clinical mobilization of [CD34.sup.+] 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.sup.+] 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.sup.+] cells. BM [c-kit.sup.+] 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.sup.+] 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.
ISSN:0021-9738