Biologically-active laminin-111 fragment that modulates the epithelial-to-mesenchymal transition in embryonic stem cells.
The dynamic interplay between the extracellular matrix and embryonic stem cells (ESCs) constitutes one of the key steps in understanding stem cell differentiation in vitro. Here we report a biologically-active laminin-111 fragment generated by matrix metalloproteinase 2 (MMP2) processing, which is highly up-regulated during differentiation. We show that the β1-chain-derived fragment interacts via α3β1-integrins, thereby triggering the down-regulation of MMP2 in mouse and human ESCs. Additionally, the expression of MMP9 and E-cadherin is up-regulated in mouse ESCs--key players in the epithelial-to-mesenchymal transition. We also demonstrate that the fragment acts through the α3β1-integrin/extracellular matrix metalloproteinase inducer complex. This study reveals a previously unidentified role of laminin-111 in early stem cell differentiation that goes far beyond basement membrane assembly and a mechanism by which an MMP2-cleaved laminin fragment regulates the expression of E-cadherin, MMP2, and MMP9.
Departments of Materials, Bioengineering, Life Sciences, and Chemical Engineering, and Institute for Biomedical Engineering, Imperial College London, London SW7 2AZ, United Kingdom.
Christine-Maria
CM
Horejs
Andrea
A
Serio
Alan
A
Purvis
Adam J
AJ
Gormley
Sergio
S
Bertazzo
Anna
A
Poliniewicz
Alex J
AJ
Wang
Peter
P
DiMaggio
Erhard
E
Hohenester
Molly M
MM
Stevens
D000818:Animals; D051926:Basigin / Q000378:metabolism; D001665:Binding Sites; D015820:Cadherins / Q000378:metabolism; D002448:Cell Adhesion; D053595:Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism*; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics; D005786:Gene Expression Regulation; D006801:Humans; D039201:Integrin alpha3beta1 / Q000378:metabolism; D007797:Laminin / Q000378:metabolism*; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D010446:Peptide Fragments / Q000378:metabolism*; D011485:Protein Binding; D015398:Signal Transduction; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000378:metabolism
C497887:Bsg protein, mouse; D015820:Cadherins; D039201:Integrin alpha3beta1; D007797:Laminin; D010446:Peptide Fragments; D019715:Tissue Inhibitor of Metalloproteinase-1; D019716:Tissue Inhibitor of Metalloproteinase-2; D051926:Basigin; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9