Hypertrophic Scar Cells Fail to Undergo a Form of Apoptosis Specific to Contractile Collagen—The Role of Tissue Transglutaminase

Abstract

Failure of apoptosis has been postulated to cause the hypercellularity and thus excess scar-tissue formation of hypertrophic scars (HTS). Here, we have examined the susceptibility of fibroblasts derived from normal or HTS to apoptosis induced during collagen-gel contraction, a wound-healing model. Normal scar (NS) fibroblasts underwent significant apoptosis (>40% total) in contractile collagen, whereas apoptosis was not detected in HTS cells. This inability was specific to apoptosis induced by contractile collagen because apoptosis could be induced using diverse modalities. Since chronic fibrotic tissue is known to be excessively cross-linked, we next examined whether collagen matrix that had been conditioned by HTS fibroblasts became refractory to enzymatic breakdown and indeed, found that it is resistant to breakdown by both collagenase D and matrix metalloproteinase-2. Newly formed extracellular matrix is stabilized by the enzyme, tissue transglutaminase, which we demonstrated to be overexpressed by HTS fibroblasts in vivo and in vitro. Reducing tissue transglutaminase activity in collagen gels containing HTS fibroblasts permitted induction of apoptosis on gel contraction, whereas increasing enzymic activity in NS cell-containing gels completely abrogated collagen-contraction-induced-apoptosis. Together, these observations show that HTS fibroblasts exhibit resistance to a specific form of apoptosis elicited by contraction of collagen gels, and that this phenomenon is dependent on excess activity of cell surface tissue transglutaminase.

A novel hydrogel-collagen composite improves functionality of an injectable extracellular matrix

“…Contraction in vitro is a function of both the mechanical force required to cause contraction and the total number of fibroblasts needed to apply a given force [40]. Thus it is reasonable to suggest that a stiffer material will require more fibroblasts to produce contraction.…”

“…Fragmented collagen and GAG have been shown to induce proliferative, fibrotic and immune responses [40]. As a cell transplant delivery system we were interested to learn if this composite system would be able to withstand specific degradation by collagenase.…”

Circulating Fibrocytes—Biology and Mechanisms in Wound Healing and Scar Formation

“…Linge et al could show that hypertrophic scar fibroblasts show resistance to a specific apoptosis form induced by the contraction of collagen lattices. This phenomenon depended on the activity of cell surface tissue transglutaminase (Linge et al, 2005). Briefly summarized, these studies indicate that delayed disappearance of fibroblasts and myofibroblasts can result in pathological and hypertrophic scar formation.…”

Role of Secreted Frizzled-related Protein 1 (SFRP1) in Wound Healing

“…Reduced fibroblast apoptosis was found to correlate with enhanced scarring (Linge et al, 2005). Previous studies have demonstrated that scar formation in the palate was responsible for the resistance to dental arch expansion or transverse and anterior-posterior growth of alveolar bone after palatal surgery in orthodontic treatment or cleft palate patients (Ishikawa et al, 1998;Chu et al, 2000).…”