MT1-MMP and RECK are involved in human CD34+ 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+ 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.
Vagima
Yaron
Y
Immunology Department,Weizmann Institute of Science, Hertzl Str., Rehovot, Israel.
Avigdor
Abraham
A
Goichberg
Polina
P
Shivtiel
Shoham
S
Tesio
Melania
M
Kalinkovich
Alexander
A
Golan
Karin
K
Dar
Ayelet
A
Kollet
Orit
O
Petit
Isabelle
I
Perl
Orly
O
Rosenthal
Ester
E
Resnick
Igor
I
Hardan
Izhar
I
Gellman
Yechiel N
YN
Naor
David
D
Nagler
Arnon
A
Lapidot
Tsvee
T
D000818:Animals; D015703:Antigens, CD / Q000032:analysis; D018952:Antigens, CD34 / Q000032:analysis*; D001854:Bone Marrow Cells / Q000502:physiology; D002465:Cell Movement / Q000502:physiology; D002633:Chemotaxis; D002678:Chimera / Q000235:genetics; D058851:GPI-Linked Proteins; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology*; D019650:Hematopoietic Stem Cell Mobilization; D006412:Hematopoietic Stem Cells / Q000187:drug effects / Q000276:immunology / Q000502:physiology*; D006801:Humans; D053511:Matrix Metalloproteinase 14 / Q000172:deficiency / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics
D015703:Antigens, CD; D018952:Antigens, CD34; D058851:GPI-Linked Proteins; D008562:Membrane Glycoproteins; C115460:RECK protein, human; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D016179:Granulocyte Colony-Stimulating Factor; D053511:Matrix Metalloproteinase 14