Fibroblast cytoskeletal remodeling contributes to connective tissue tension

Department of Neurology, University of Vermont, Burlington, Vermont 05405, USA.
Journal of Cellular Physiology (Impact Factor: 3.87). 05/2011; 226(5):1166-75. DOI: 10.1002/jcp.22442
Source: PubMed

ABSTRACT The visco-elastic behavior of connective tissue is generally attributed to the material properties of the extracellular matrix rather than cellular activity. We have previously shown that fibroblasts within areolar connective tissue exhibit dynamic cytoskeletal remodeling within minutes in response to tissue stretch ex vivo and in vivo. Here, we tested the hypothesis that fibroblasts, through this cytoskeletal remodeling, actively contribute to the visco-elastic behavior of the whole tissue. We measured significantly increased tissue tension when cellular function was broadly inhibited by sodium azide and when cytoskeletal dynamics were compromised by disrupting microtubules (with colchicine) or actomyosin contractility (via Rho kinase inhibition). These treatments led to a decrease in cell body cross-sectional area and cell field perimeter (obtained by joining the end of all of a fibroblast's processes). Suppressing lamellipodia formation by inhibiting Rac-1 decreased cell body cross-sectional area but did not affect cell field perimeter or tissue tension. Thus, by changing shape, fibroblasts can dynamically modulate the visco-elastic behavior of areolar connective tissue through Rho-dependent cytoskeletal mechanisms. These results have broad implications for our understanding of the dynamic interplay of forces between fibroblasts and their surrounding matrix, as well as for the neural, vascular, and immune cell populations residing within connective tissue.

Download full-text


Available from: James C Iatridis, Oct 15, 2014
  • Source
    • "Importantly, this change in fibroblast shape is accompanied by a lowering of connective tissue tension [Langevin et al., 2011]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The biomechanical behavior of connective tissue in response to stretching is generally attributed to the molecular composition and organization of its extracellular matrix. It also is becoming apparent that fibroblasts play an active role in regulating connective tissue tension. In response to static stretching of the tissue, fibroblasts expand within minutes by actively remodeling their cytoskeleton. This dynamic change in fibroblast shape contributes to the drop in tissue tension that occurs during viscoelastic relaxation. We propose that this response of fibroblasts plays a role in regulating extracellular fluid flow into the tissue, and protects against swelling when the matrix is stretched. This article reviews the evidence supporting possible mechanisms underlying this response including autocrine purinergic signaling. We also discuss fibroblast regulation of connective tissue tension with respect to lymphatic flow, immune function and cancer. J. Cell. Biochem. © 2013 Wiley Periodicals, Inc.
    Journal of Cellular Biochemistry 08/2013; 114(8). DOI:10.1002/jcb.24521 · 3.37 Impact Factor
  • Source
    • "Fibroblasts in culture and in vivo respond to mechanical loads with measurable effects, such as extracellular calcium influx (through stretch-activated membrane channels), calcium-induced release of intracellular calcium stores, and the release of ATP. These studies indicate that tissue contraction and relaxation may result in a dynamic, body-wide pattern of cellular activity (Langevin et al., 2011, 2010). Furthermore the morphology of the embedded fibroblast changes from lamellar to dendritic, depending on the tensional status of the fascial network (Grinnell, 2000, 2007, 2008). "
    [Show abstract] [Hide abstract]
    ABSTRACT: More than 100 years ago AT Still MD founded osteopathic medicine, and specifically described fascia as a covering, with common origins of layers of the fascial system despite diverse names for individual parts. Fascia assists gliding and fluid flow and is highly innervated. Fascia is intimately involved with respiration and with nourishment of all cells of the body, including those of disease and cancer. This paper reviews information presented at the first three International Fascia Research Congresses in 2007, 2009 and 2012 from the perspective of Dr Still, that fascia is vital for organism's growth and support, and it is where disease is sown.
    Journal of bodywork and movement therapies 07/2013; 17(3):356-64. DOI:10.1016/j.jbmt.2013.05.015
  • Source
    • "This includes patients with low back pain that have increased thickness and echogenicity of the connective tissues forming the thoracolumbar fascia and impaired mobility between the areolar and dense layers (Langevin et al., 2009; Langevin et al., 2011b). Our current results suggest that cells in the denser connective tissues may not have the capacity to adjust resting tension as dynamically as in less dense connective tissue (Langevin et al., 2011a). "
    [Show abstract] [Hide abstract]
    ABSTRACT: In areolar "loose" connective tissue, fibroblasts remodel their cytoskeleton within minutes in response to static stretch resulting in increased cell body cross-sectional area that relaxes the tissue to a lower state of resting tension. It remains unknown whether the loosely arranged collagen matrix, characteristic of areolar connective tissue, is required for this cytoskeletal response to occur. The purpose of this study was to evaluate cytoskeletal remodeling of fibroblasts in, and dissociated from, areolar and dense connective tissue in response to 2 h of static stretch in both native tissue and collagen gels of varying crosslinking. Rheometric testing indicated that the areolar connective tissue had a lower dynamic modulus and was more viscous than the dense connective tissue. In response to stretch, cells within the more compliant areolar connective tissue adopted a large "sheet-like" morphology that was in contrast to the smaller dendritic morphology in the dense connective tissue. By adjusting the in vitro collagen crosslinking, and the resulting dynamic modulus, it was demonstrated that cells dissociated from dense connective tissue are capable of responding when seeded into a compliant matrix, while cells dissociated from areolar connective tissue can lose their ability to respond when their matrix becomes stiffer. This set of experiments indicated stretch-induced fibroblast expansion was dependent on the distinct matrix material properties of areolar connective tissues as opposed to the cells' tissue of origin. These results also suggest that disease and pathological processes with increased crosslinks, such as diabetes and fibrosis, could impair fibroblast responsiveness in connective tissues. J. Cell. Physiol. 228: 50-57, 2013. © 2012 Wiley Periodicals, Inc.
    Journal of Cellular Physiology 01/2013; 228(1):50-7. DOI:10.1002/jcp.24102 · 3.87 Impact Factor
Show more