Wound healing is a complex biological process that requires coordination among multiple cell types and the dynamic extracellular matrix (ECM) microenvironment in four sequential phases: hemostasis, inflammation, proliferation, and remodeling. Although the hemostatic, inflammatory, and to some extent the proliferative phases of wound healing have been well studied, the regulation of the remodeling phase has received less attention. In the remodeling phase, the angiogenic process is complete and anti-angiogenic mechanisms play a key role in removing unnecessary vessels. Vessel regression occurs simultaneously with ECM remodeling, a process that reorganizes and reinforces matrix components to achieve mechanical strength. In most wounds, the end result of wound healing is scar formation, as the ECM never fully returns to normal architecture. Our long term goal is to understand the factors that regulate wound resolution and scar formation. Preliminary studies in our lab demonstrate that pigment epithelium-derived factor (PEDF) is an important endogenous factor that regulates vascular regression in remodeling wounds. Recent studies suggest that PEDF may also have significant interactions with cell types other than endothelial cells (EC), including fibroblasts. Moreover, the effect of PEDF may be influenced by its binding to ECM molecules such as collagen I, collagen III, and heparin. The current proposal will explore the mechanisms by which PEDF influences wound vasculature and scar formation. The central hypothesis of this proposal is that PEDF works through various ECM binding partners to both regulate vessel regression and scar formation during healing.
The specific aims of this study are 1) to determine the influence of PEDF on wound angiogenesis and scar formation, 2) to analyze the distribution of PEDF receptors in the wound, and 3) to investigate the specific functional interactions between PEDF and its ECM binding partners in wounds.
Aim 1 will involve in vivo studies of wound healing in PEDF-/- mice to determine PEDF's function as an anti-angiogenic and ECM remodeling factor.
In Aim 2, immunohistochemical and indirect immunofluorescence studies will localize known PEDF receptors to major cell types that are involved in wound healing.
Aim 3 will involve gain-of-function studies utilizing ECM-PEDF complexes. These studies will determine the synergistic effect of ECM bound PEDF on wound healing outcomes, including blood vessel growth and regression, ECM maturation, scar formation, and wound breaking strength. These experiments will provide insight into the mechanisms that regulate the remodeling phase of dermal wound healing, and may suggest future therapeutic options for tissue regeneration, fibrosis and cancer.
Angiogenesis and scar formation are crucial aspects of the wound healing process. As wounds heal, certain factors ensure a balanced resolution to the repair process by controlling the number of blood vessels formed as well as connective tissue remodeling. One such factor is Pigment Epithelium-Derived Factor (PEDF), and this study aims to explore the mechanisms by which PEDF influences wound vasculature and scar formation. Understanding PEDF's function in the wounds will shed light on potential therapeutic options to decrease scarring and promote regeneration. Ultimately, these studies will spur advances in regenerative medicine and in more effective therapies against fibrosis and tumorigenesis.
| Michalczyk, Elizabeth R; Chen, Lin; Fine, David et al. (2018) Pigment Epithelium-Derived Factor (PEDF) as a Regulator of Wound Angiogenesis. Sci Rep 8:11142 |
