The repair of wounds usually terminates with a scar. The healing from a severe tissue loss can create a new clinical problem, excessive scarring. Approaches to prevent excessive scarring will optimize the repair process. Controlling gap-junction communications between cells and/or the transport of the proteins that form gap junctions offers new approaches for controlling this problem.
Recent Advances:
Gap-junctional intercellular communication (GJIC) requires hemichannels, connexon structures, embedded in the plasma membrane of coupled cells. The connexon is composed of six proteins from the connexin (Cx) family. The docking of connexons between the neighboring cells forms a gated channel, where small molecules can pass directly between the cytoplasm of cells. In wound repair, GJIC between fibroblasts in granulation tissue advances wound repair. Also, the GJIC between mast cells and fibroblasts during the remodeling phase of repair may explain how mast cells promote excessive scarring. In addition, Cx can affect transforming growth factor beta (TGF-β) intracellular signaling through its shared binding site on microtubules within fibroblasts.
Critical Issues:
Can excessive scarring be controlled through limiting the local amassing of mast cells or preventing their interactions with wound fibroblasts through GJIC?
Future Directions:
The prevention of the accumulation of mast cells in granulation tissue or interfering with their communications via GJIC with fibroblasts offers new approaches for preventing excess scarring. The association of Cx with microtubules altering TGF-β signaling presents a new target for improving the quality of repair as well as the deposition of unnecessary fibrosis.
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References
1.
EhrlichHP, KelleySF. Hypertrophic scar: an interruption in the remodeling of repair—a laser Doppler blood flow study. Plast Reconstr Surg, 1992; 90:993.
2.
EhrlichHP, DesmouliereA, DiegelmannRF, CohenIK, ComptonCC, GarnerWL, KapanciY, GabbianiG. Morphological and immunochemical differences between keloid and hypertrophic scar. Am J Pathol, 1994; 145:105.
3.
DesmouliereA, RedardM, DarbyI, GabbianiG. Apoptosis mediates the decrease in cellularity during the transition between granulation tissue and scar. Am J Pathol, 1995; 146:56.
4.
KischerCW, BaileyJF. The mast cell in hypertrophic scars. Tex Rep Biol Med, 1972; 30:327.
LaskinDL, SunilVR, GardnerCR, LaskinJD. Macrophages and tissue injury: agents of defense or destruction?Ann Rev Pharmacol Toxicol, 2011; 51:267.
7.
LiuW, WangDR, CaoYL. TGF-beta: a fibrotic factor in wound scarring and a potential target for anti-scarring gene therapy. Curr Gene Ther, 2004; 4:123.
8.
DesmouliereA, GeinozA, GabbianiF, GabbianiG. Transforming growth factor-beta 1 induces alpha-smooth muscle actin expression in granulation tissue myofibroblasts and in quiescent and growing cultured fibroblasts. J Cell Biol, 1993; 122:103.
9.
RobertsAB, SpornMB. Transforming growth factor-beta: potential common mechanisms mediating its effects on embryogenesis, inflammation-repair, and carcinogenesis. Int J Rad Appl Instrum B, 1987; 14:435.
10.
ChinKY. Connexins, a new target in wound treatment. J Wound Care, 2011; 20:386.
11.
ZhuKQ, CarrougherGJ, GibranNS, IsikFF, EngravLH. Review of the female Duroc/Yorkshire pig model of human fibroproliferative scarring. Wound Repair Regen, 2007; 15,Suppl 1:S32.
12.
WangJ, DingJ, JiaoH, HonardoustD, MomtaziM, ShankowskyHA, TredgetEE. Human hypertrophic scar-like nude mouse model: characterization of the molecular and cellular biology of the scar process. Wound Repair Regen, 2011; 19:274.
13.
GabbianiG, ChaponnierC, HuttnerI. Cytoplasmic filaments and gap junctions in epithelial cells and myofibroblasts during wound healing. J Cell Biol, 1978; 76:561.
14.
AuSR, AuK, SaggersGC, KarneN, EhrlichHP. Rat mast cells communicate with fibroblasts via gap junction intercellular communications. J Cell Biochem, 2007; 100:1170.
15.
KumarNM, GilulaNB. The gap junction communication channel. Cell, 1996; 84:381.
16.
CoutinhoP, QiuC, FrankS, TamberK, BeckerD. Dynamic changes in connexin expression correlate with key events in the wound healing process. Cell Biol Int, 2003; 27:525.
GailitJ, MarcheseMJ, KewRR, GruberBL. The differentiation and function of myofibroblasts is regulated by mast cell mediators. J Invest Dermatol, 2001; 117:1113.
20.
GaoF, ZhaoY, FengYQ, HuoR, XueWJ, WangFG, LvRR, XueF, LiQ, ZhangJ. [Expression of mast cell tryptase in scar]Zhonghua Zheng Xing Wai Ke Za Zhi, 2010; 26:132.
21.
FoleyTT, SaggersGC, MoyerKE, EhrlichHP. Rat mast cells enhance fibroblast proliferation and fibroblast-populated collagen lattice contraction through gap junctional intercellular communications. Plast Reconstr Surg, 2011; 127:1478.
22.
Oviedo-OrtaE, HoyT, EvansWH. Intercellular communication in the immune system: differential expression of connexin40 and 43, and perturbation of gap junction channel functions in peripheral blood and tonsil human lymphocyte subpopulations. Immunology, 2000; 99:578.
23.
Oviedo-OrtaE, GasqueP, EvansWH. Immunoglobulin and cytokine expression in mixed lymphocyte cultures is reduced by disruption of gap junction intercellular communication. FASEB J, 2001; 15:768.
24.
Oviedo-OrtaE, ErringtonRJ, EvansWH. Gap junction intercellular communication during lymphocyte transendothelial migration. Cell Biol Int, 2002; 26:253.
25.
GoligerJA, PaulDL. Wounding alters epidermal connexin expression and gap junction-mediated intercellular communication. Mol Biol Cell, 1995; 6:1491.
26.
KretzM, EuwensC, HombachS, EckardtD, TeubnerB, TraubO, WilleckeK, OttT. Altered connexin expression and wound healing in the epidermis of connexin-deficient mice. J Cell Sci, 2003; 116:3443.
27.
EhrlichHP, DiezT. Role for gap junctional intercellular communications in wound repair. Wound Repair Regen, 2003; 11:481.
28.
MoyerKE, DavisA, SaggersGC, MackayDR, EhrlichHP. Wound healing: the role of gap junctional communication in rat granulation tissue maturation. Exp Mol Pathol, 2002; 72:10.
29.
RichardsTS, DunnCA, CarterWG, UsuiML, OlerudJE, LampePD. Protein kinase C spatially and temporally regulates gap junctional communication during human wound repair via phosphorylation of connexin43 on serine368. J Cell Biol, 2004; 167:555.
30.
BellE, IvarssonB, MerrillC. Production of a tissue-like structure by contraction of collagen lattices by human fibroblasts of different proliferative potential in vitro. Proc Natl Acad Sci USA, 1979; 76:1274.
31.
EhrlichHP, GabbianiG, MedaP. Cell coupling modulates the contraction of fibroblast-populated collagen lattices. J Cell Physiol, 2000; 184:86.
32.
BowmanNN, DonahueHJ, EhrlichHP. Gap junctional intercellular communication contributes to the contraction of rat osteoblast populated collagen lattices. J Bone Miner Res, 1998; 13:1700.
33.
EhrlichHP, SunB, SaggersGC, KromathF. Gap junction communications influence upon fibroblast synthesis of Type I collagen and fibronectin. J Cell Biochem, 2006; 98:735.
34.
HirschiKK, BurtJM, HirschiKD, DaiC. Gap junction communication mediates transforming growth factor-beta activation and endothelial-induced mural cell differentiation. Circ Res, 2003; 93:429.
35.
MontesanoR, OrciL. Transforming growth factor beta stimulates collagen-matrix contraction by fibroblasts: implications for wound healing. Proc Natl Acad Sci USA, 1988; 85:4894.
ItohS, ItohF, GoumansMJ, Ten DijkeP. Signaling of transforming growth factor-beta family members through Smad proteins. Eur J Biochem, 2000; 267:6954.
38.
DaCosta ByfieldS, MajorC, LapingNJ, RobertsAB. SB-505124 is a selective inhibitor of transforming growth factor-beta type I receptors ALK4, ALK5, and ALK7. Mol Pharmacol, 2004; 65:744.
39.
AuK, EhrlichHP. When the Smad signaling pathway is impaired, fibroblasts advance open wound contraction. Exp Mol Pathol, 2010; 89:236.
40.
DaiP, NakagamiT, TanakaH, HitomiT, TakamatsuT. Cx43 mediates TGF-beta signaling through competitive Smads binding to microtubules. Mol Biol Cell, 2007; 18:2264.
41.
YamamotoT, HartmannK, EckesB, KriegT. Mast cells enhance contraction of three-dimensional collagen lattices by fibroblasts by cell-cell interaction: role of stem cell factor/c-kit. Immunology, 2000; 99:435.
42.
ButterfieldJH, WeilerD, DewaldG, GleichGJ. Establishment of an immature mast cell line from a patient with mast cell leukemia. Leuk Res, 1988; 12:345.
KoibuchiY, IchikawaA, NakagawaM, TomitaK. Histamine release induced from mast cells by active components of compound 48/80. Eur J Pharmacol, 1985; 115:163.
45.
FoleyTT, EhrlichHP. Through gap junction communications, co-cultured mast cells, fibroblasts generate fibroblast activates allied with hypertrophic scarring. Plast Reconstr Surg, 2013(in press).
46.
PistorioAL, EhrlichHP. Modulatory effects of connexin-43 expression on gap junction intercellular communications with mast cells and fibroblasts. J Cell Biochem, 2011; 112:1441.
47.
IbukiN, YamaokaY, SawaY, KawasakiT, YoshidaS. Different expressions of connexin 43 and 32 in the fibroblasts of human dental pulp. Tissue Cell, 2002; 34:170.
