Regulation of fibroblast function in wound repair

Wound healing is a complex, orchestrated process required for the maintenance of developing and adult organisms. Aberrant, delayed, or unsuccessful wound healing contributes to a high percentage of mortality and morbidity within our society. For wound repair to be successful, the recruitment, proliferation, and retention of fibroblasts are required. Dermal fibroblasts within the disturbed locale contribute to extracellular matrix degradation, remodeling, and ultimate contraction of the wound. Signaling via the EGFR plays an important role in migration and proliferation of fibroblasts and epithelial cells during wound healing. Unfortunately, current understanding of control mechanisms for fibroblast motility into the wound bed via the extracellular matrix and ultimate proliferation is not complete. Further, knowledge of cell signaling regulation during fibroblast aging is nascent. This work, herein, describes investigations into the Epidermal Growth Factor Receptor (EGFR) signaling cascade of fibroblasts as it relates to the EGF-like repeats of the extracellular matrix protein, tenascin-C, and the EGFR cascade as it pertains to senescence-associated alterations. Tenascin-C is unique in that its expression is temporally and spatially restricted and tied to moments requiring mitogenesis and motility. Within each arm of the hexameric macro-protein are 14.5 EGF-like repeats of obscure function. This work describes the first definitive proof that ECM proteins can signal directly to growth factor receptors as ligands, suggesting a novel mode of signaling from the ECM directing cell motility via “matrikines.” Utilizing the extremely low affinity EGF-like repeats, we were able to test basic hypothesese related to cell signal partitioning. We were able to show that signal promotion restricted mainly to the cell surface as opposed to the endosome was preferential for cell migration as compared to proliferation. Within the geriatric population, a mounting deficiency in wound healing leads to increased complications and death. The causes for this aging-associated decrement in wound healing are obscure. As fibroblasts approach senescence, their migratory and proliferative capacities diminish, suggesting one root cause of aging-associated incompetence. This diminishment is tied to a decrement in EGFR levels and signaling at the level of the receptor. We investigated the causes of this EGFR signaling deficiency. Our final work describes an elevated protein tyrosine phosphatase mechanism attenuating EGFR signaling within aged cells, with eventual increases in levels of Shp-1 and PTP1B. This work, in its entirety, supports a wound healing model in which ECM components like tenascin-C are laid down and signal through growth factor receptors to initiate migration preferentially from the cell surface compartment. It further supports the notion that during senescence EGFR is attenuated by enhanced PTP activity to blunt the migratory and proliferative signals during wound healing.