MMP-2, MT1-MMP, and TIMP-2 are essential for the invasive capacity of human mesenchymal stem cells: differential regulation by inflammatory cytokines.
Human mesenchymal stem cells (hMSCs) represent promising tools in various clinical applications, including the regeneration of injured tissues by endogenous or transplanted hMSCs. The molecular mechanisms, however, that control hMSC mobilization and homing which require invasion through extracellular matrix (ECM) barriers are almost unknown. We have analyzed bone marrow-derivedhMSCs and detected strong expression and synthesis of matrix metalloproteinase 2 (MMP-2), membrane type 1 MMP (MT1-MMP), tissue inhibitor of metalloproteinase 1 (TIMP-1), and TIMP-2. The ability of hMSCs to traverse reconstituted human basement membranes was effectively blocked in the presence of synthetic MMP inhibitors. Detailed studies by RNA interference revealed that gene knock-down of MMP-2, MT1-MMP, or TIMP-2 substantially impaired hMSC invasion, whereas silencing of TIMP-1 enhanced cell migration, indicating opposing roles of both TIMPs in this process. Moreover, the inflammatory cytokines TGF-beta1, IL-1beta, and TNF-alpha up-regulated MMP-2, MT1-MMP, and/or MMP-9 production in these cells, resulting in a strong stimulation of chemotactic migration through ECM, whereas the chemokine SDF-1alpha exhibited minor effects on MMP/TIMP expression and cell invasion. Thus, induction of specific MMP activity in hMSCs by inflammatory cytokines promotes directed cell migration across reconstituted basement membranes in vitro providing a potential mechanism in hMSC recruitment and extravasation into injured tissues in vivo.
Ries
Christian
C
Division of Clinical Chemistry and Clinical Biochemistry, Surgical Department, Ludwig-Maximillians-University of Munich, Nussbaumstrasse 20, 80336 Munich, Germany. christian.ries@med.uni-muenchen.de
Egea
Virginia
V
Karow
Marisa
M
Kolb
Helmut
H
Jochum
Marianne
M
Neth
Peter
P
D001854:Bone Marrow Cells / Q000166:cytology / Q000378:metabolism*; D002460:Cell Line; D002633:Chemotaxis / Q000187:drug effects / Q000502:physiology*; D016207:Cytokines / Q000494:pharmacology; D005109:Extracellular Matrix / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000378:metabolism; D053511:Matrix Metalloproteinase 14 / Q000096:biosynthesis* / Q000235:genetics; D020778:Matrix Metalloproteinase 2 / Q000096:biosynthesis* / Q000235:genetics; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000378:metabolism*; D034622:RNA Interference; D012038:Regeneration / Q000187:drug effects / Q000502:physiology; D033581:Stem Cell Transplantation; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000096:biosynthesis* / Q000235:genetics
D016207:Cytokines; D019716:Tissue Inhibitor of Metalloproteinase-2; D020778:Matrix Metalloproteinase 2; C507086:MMP14 protein, human; D053511:Matrix Metalloproteinase 14