Mechanisms of 3-D migration and matrix remodeling of fibroblasts within artificial ECMs.
The elucidation of molecular cell-extracellular matrix (ECM) interactions regulating tissue dynamics necessitates straightforward model systems that can dissect the associated physiological complexity into a smaller number of distinct interactions. Here we employ a previously developed artificial ECM model system to study dynamic cell-matrix interactions involved in proteolytic three-dimensional (3-D) migration and matrix remodeling at the level of single cells. Quantitative time-lapse microscopy of primary human fibroblasts exposed to exogenous physiological matrix metalloproteinase (MMP) inhibitors revealed that 3-D migration is dependent on cell seeding density and occurred via highly localized MMP- and tissue inhibitor of metalloproteinases-2-dependent processes. Stimulation of cells by tumor necrosis factor alpha led to a striking augmentation in fibroblast migration that was accompanied by induction of alphaVbeta3 integrin expression. In long-term cultures, extensive localized cellular matrix remodeling resulted in the morphogenesis of single cells into interconnected multicellular networks. Therefore, these tailor-made artificial ECMs can replicate complex 3-D cell-matrix interactions involved in tissue development and regeneration, an important step in the design of next-generation synthetic biomaterials for tissue engineering.
Raeber
G P
GP
Institute of Bioengineering and Institute of Chemical Sciences and Engineering, Ecole Polytechnique Fédérale de Lausanne, CH-1015 Lausanne, Switzerland.
Lutolf
M P
MP
Hubbell
J A
JA
D040761:Biomimetic Materials / Q000378:metabolism*; D002465:Cell Movement / Q000502:physiology*; D002478:Cells, Cultured; D005109:Extracellular Matrix / Q000502:physiology*; D016326:Extracellular Matrix Proteins / Q000378:metabolism*; D005347:Fibroblasts / Q000166:cytology* / Q000502:physiology*; D006801:Humans; D021621:Imaging, Three-Dimensional; D020782:Matrix Metalloproteinases / Q000378:metabolism*
D016326:Extracellular Matrix Proteins; D020782:Matrix Metalloproteinases