Extracellular Matrix and Dermal Fibroblast Function in the Healing Wound

Abstract

Significance: Fibroblasts play a critical role in normal wound healing. Various extracellular matrix (ECM) components, including collagens, fibrin, fibronectin, proteoglycans, glycosaminoglycans, and matricellular proteins, can be considered potent protagonists of fibroblast survival, migration, and metabolism. Recent Advances: Advances in tissue culture, tissue engineering, and ex vivo models have made the examination and precise measurements of ECM components in wound healing possible. Likewise, the development of specific transgenic animal models has created the opportunity to characterize the role of various ECM molecules in healing wounds. In addition, the recent characterization of new ECM molecules, including matricellular proteins, dermatopontin, and FACIT collagens (Fibril-Associated Collagens with Interrupted Triple helices), further demonstrates our cursory knowledge of the ECM in coordinated wound healing. Critical Issues: The manipulation and augmentation of ECM components in the healing wound is emerging in patient care, as demonstrated by the use of acellular dermal matrices, tissue scaffolds, and wound dressings or topical products bearing ECM proteins such as collagen, hyaluronan (HA), or elastin. Once thought of as neutral structural proteins, these molecules are now known to directly influence many aspects of cellular wound healing. Future Directions: The role that ECM molecules, such as CCN2, osteopontin, and secreted protein, acidic and rich in cysteine, play in signaling homing of fibroblast progenitor cells to sites of injury invites future research as we continue investigating the heterotopic origin of certain populations of fibroblasts in a healing wound. Likewise, research into differently sized fragments of the same polymeric ECM molecule is warranted as we learn that fragments of molecules such as HA and tenascin-C can have opposing effects on dermal fibroblasts.

E. J. Caterson, MD, PhD

Figure 1.

The extracellular matrix (ECM) of normal skin with selected components depicted. Fiber-forming proteins and collagens define the rigid mechanical structure of skin, while elastic fibers enable stretching. Proteoglycans and glycoproteins create an osmotically active hydrated interstitial space. Matricellular proteins do not contribute to the mechanical structure of the ECM but instead act as paracrine signaling molecules. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/wound

Figure 2.

ECM components implicated in fibrosis or hypertrophic scarring. Overexpression or modification of certain ECM components is associated with myofibroblast differentiation and fibrotic wound healing.

Figure 3.

The appearance of ECM proteins correlates with phases of wound healing. The ECM composition of a wound changes as it progresses through the hemostatic, inflammatory, proliferative, and remodeling phases of healing. Fibrin, fibronectin, and other clotting proteins dominate in the hemostatic acute wound, but as fibroblasts migrate into the wound they produce proteoglycans and collagen that are associated with mature healing wounds. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/wound

Figure 4.

Glycosylated matrix proteins impair and delay healing of diabetic wounds. Many factors, including reduced vasculogenesis, impair the healing of diabetic wounds. The presence of advanced glycosylation end products in diabetic wounds is also associated with decreased collagen production, migration, and proliferation of fibroblasts.

Figure 5.

Histological evaluation of wound contraction and collagen fiber orientation in a healing full-thickness excisional porcine wound stained with Masson Trichrome (collagen appears blue). (A) After 7 days of healing, the wound is contracted and loosely organized collagen is present in granulation tissue. (B) 14 days after wounding, the wound is re-epithelialized with reduced contraction and gradual re-modeling of collagen fibers. (C) Intact porcine skin demonstrates highly organized collagen bundles and fibers in dermis. All images are taken with a 20×objective. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/wound