Cytokines modulated myofibroblast induction and force generation in dupuytren's fibroblasts; Lessons for tissue engineering?

Tissue engineering aims to get cells in vitro to lay down collagen and generate living functional 3D structures for implantation. The major challenge is getting fibroblasts to lay down functional collagen in vitro. We studied a natural condition where fibroblasts secrete excess collagen and shorten the matrix by remodelling it (Dupuytren’s disease). Some of the collagen layed down is organised and has the structure of tendon (cord) but the active state is the nodule. The cells responsible for the fibrotic contractures seen in Dupuytren’s disease are the myofibroblasts, expressing α-smooth muscle actin (α-SMA), correlating with increased deposition of extracellular matrix (ECM) components1 and contractile force generation, contracting the ECM2. Cytokines are potential targets for myofibroblast modulation, as they control expression of myofibroblast marker α-SMA3. We have examined the effect of cytokines, TGF-β1 and PDGF-BB, on force generation and matrix remodeling

Isometric contraction of dupuytren's myofibroblasts is inhibited by blocking intercellular junctions

Myofibroblasts (MFs) are responsible for both physiological wound and scar contraction. However, it is not known whether these cells act individually to contract the surrounding matrix or whether they behave in a coordinated manner. Therefore, we studied intercellular junctions of primary human MFs derived from patients with Dupuytren's disease, a fibrotic disorder of the dermis and subdermal tissues of the palm. The cells were maintained in anchored three-dimensional collagen lattices to closely mimic conditions in vivo. We found that selective blockade of adherens, mechanosensitive, or gap junctions effectively inhibited contraction of the collagen matrices and downregulated the MF phenotype. Our data indicate that MFs in part function as a coordinated cellular syncytium, and disruption of intercellular communication may provide a therapeutic target in diseases characterized by an overabundance of these contractile cells. © 2013 The Society for Investigative Dermatology