Cellular control of connective tissue matrix tension

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.

Copyright © 2013 Wiley Periodicals, Inc.

Figures

Figure 1

Role of fibroblasts in promoting fluid flux into the tissue during acute inflammation (Adapted from Reed et al. [11, 12]). A: In areolar connective tissue, the loose collagen mesh is filled with polyanionic glycosaminoglycans that attract large quantities of water. In the absence of inflammation, active tension exerted by fibroblasts onto the collagen network keeps the tissue under-hydrated by restraining the matrix, keeping pore size small and restricting water entry into the tissue. B: In the early stages of acute inflammation, inflammatory mediators cause the rupture of cell matrix contacts. This unrestrains the matrix, allowing fluid to enter the tissue driven by the osmotic force created by the now accessible glycosaminoglycans. Integrin blockers have a similar effect by interfering with cell-matrix contacts.

Figure 2

Proposed mechanism for fibroblast control of matrix tension and fluid flux in response to tissue stretch. A: Fibroblasts maintain tension on the extracellular matrix and prevent fluid influx into the tissue. B: Sustained stretching of the matrix for several minutes decreases matrix compaction and increase in pore size, allowing water to flow in. C: Fibroblasts “letting go” of the cell-matrix contacts would further unrestrain the matrix and cause further swelling. D: Fibroblast remodeling, expansion and maintenance of cell-matrix contacts would keep the matrix restrained and reduces water influx into the tissue.

Figure 3

Response to fibroblasts to tissue stretch ex vivo in isotonic and hypertonic tissue bath. Raising the osmolarity of the back by 20–40% (by adding bovine serum albumin) inhibited the expansion of fibroblasts in response to tissue stretch.