title: Identification of the critical therapeutic entity in secreted Hsp90α that promotes wound healing in newly re-standardized healthy and diabetic pig models.
abstract: Chronic and non-healing skin wounds represent a significant clinical, economic and social problem worldwide. Currently, there are few effective treatments. Lack of well-defined animal models to investigate wound healing mechanisms and furthermore to identify new and more effective therapeutic agents still remains a major challenge. Pig skin wound healing is close to humans. However, standardized pig wound healing models with demonstrated validity for testing new wound healing candidates are unavailable. Here we report a systematic evaluation and establishment of both acute and diabetic wound healing models in pigs, including wound-creating pattern for drug treatment versus control, measurements of diabetic parameters and the time for detecting delayed wound healing. We find that treatment and control wounds should be on the opposite and corresponding sides of a pig. We demonstrate a strong correlation between duration of diabetic conditions and the length of delay in wound closure. Using these new models, we narrow down the minimum therapeutic entity of secreted Hsp90α to a 27-amino acid peptide, called fragment-8 (F-8). In addition, results of histochemistry and immunohistochemistry analyses reveal more organized epidermis and dermis in Hsp90α-healed wounds than the control. Finally, Hsp90α uses a similar signaling mechanism to promote migration of isolated pig and human keratinocytes and dermal fibroblasts. This is the first report that shows standardized pig models for acute and diabetic wound healing studies and proves its usefulness with both an approved drug and a new therapeutic agent.
authors.affiliation: The Department of Dermatology and the Norris-USC Comprehensive Cancer Center, the Keck School of Medicine, the University of Southern California, Los Angeles, California, 90033, United States of America.
authors.forename: Kathryn
authors.initials: K
authors.lastname: O'Brien
authors.affiliation: The Department of Dermatology and the Norris-USC Comprehensive Cancer Center, the Keck School of Medicine, the University of Southern California, Los Angeles, California, 90033, United States of America.
authors.forename: Ayesha
authors.initials: A
authors.lastname: Bhatia
authors.affiliation: The Department of Dermatology and the Norris-USC Comprehensive Cancer Center, the Keck School of Medicine, the University of Southern California, Los Angeles, California, 90033, United States of America.
authors.forename: Fred
authors.initials: F
authors.lastname: Tsen
authors.affiliation: The Department of Dermatology and the Norris-USC Comprehensive Cancer Center, the Keck School of Medicine, the University of Southern California, Los Angeles, California, 90033, United States of America.
authors.forename: Mei
authors.initials: M
authors.lastname: Chen
authors.affiliation: Division of Plastic and Reconstructive Surgery, the University of Southern California, Los Angeles, California, 90033, United States of America.
authors.forename: Alex K
authors.initials: AK
authors.lastname: Wong
authors.affiliation: The Department of Dermatology and the Norris-USC Comprehensive Cancer Center, the Keck School of Medicine, the University of Southern California, Los Angeles, California, 90033, United States of America.
authors.forename: David T
authors.initials: DT
authors.lastname: Woodley
authors.affiliation: The Department of Dermatology and the Norris-USC Comprehensive Cancer Center, the Keck School of Medicine, the University of Southern California, Los Angeles, California, 90033, United States of America.
authors.forename: Wei
authors.initials: W
authors.lastname: Li
mesh_terms: D000818:Animals; D000077214:Becaplermin; D002465:Cell Movement / Q000187:drug effects; D048909:Diabetes Complications; D003921:Diabetes Mellitus, Experimental / Q000473:pathology; D018841:HSP90 Heat-Shock Proteins / Q000494:pharmacology / Q000502:physiology / Q000627:therapeutic use*; D023421:Models, Animal; D020574:Proto-Oncogene Proteins c-sis / Q000627:therapeutic use; D012867:Skin / Q000293:injuries / Q000378:metabolism / Q000473:pathology; D013552:Swine / Q000502:physiology*; D013997:Time Factors; D014945:Wound Healing / Q000187:drug effects*; D014947:Wounds and Injuries / Q000188:drug therapy
chemical_list: D018841:HSP90 Heat-Shock Proteins; D020574:Proto-Oncogene Proteins c-sis; D000077214:Becaplermin