Ceramide kinase is required for a normal eicosanoid response and the subsequent orderly migration of fibroblasts

• Type of Material: Article
• Authors: Dayanjan S. Wijesinghe, Virginia Commonwealth University; Matthew Brentnall, Virginia Commonwealth University; Jennifer A. Mietla, Virginia Commonwealth University; L. Alexis Hoeferlin, Virginia Commonwealth University; Robert F. Diegelmann, Virginia Commonwealth University; Lawrence Boise, Emory University; Charles E. Chalfant, Virginia Commonwealth University
• Language: English
• Date: 2014-07
• Publisher: American Society for Biochemistry and Molecular Biology
• Publication Version: Final Published Version
• Copyright Statement: © 2014 American Society for Biochemistry and Molecular Biology
• License: Creative Commons Attribution 3.0 Unported
• Final Published Version (URL): http://www.jlr.org/content/55/7/1298
• Title of Journal or Parent Work: Journal of Lipid Research
• ISSN: 0022-2275
• Volume: 55
• Issue: 7
• Start Page: 1298
• End Page: 1309
• Grant/Funding Information: This work was supported by the Veteran’s Administration VA Merit Award BX001792 (C.E.C.) and Research Career Scientist Award (C.E.C.), the National Institutes of Health Grants HL072925 (C.E.C.) and CA154314 (C.E.C.), the US-Israel Binational Science Foundation Grants BSF#2011380 (C.E.C.) and NH1C06-RR17393 (to Virginia Commonwealth University for renovation), National Institutes of Health National Cancer Institute Cancer Center Support Grant P30 CA016059 (to Massey Cancer Center), National Research Service Award-T32 Post-Doctoral Fellowship in Wound Healing GM008695 (D.S.W.), Career Development Award CDA1 from the Department of Veterans Affairs (D.S.W.), National Research Service Award-T31 Pre- Doctoral Fellowship in Functional Lipidomics in Cardiovascular and Respiratory Diseases HL094290 (J.A.M.), and Georgia Cancer Coalition Scholar Award (L.H.B.).; Services and products in support of the research project were generated by the Virginia Commonwealth University Massey Cancer Center Lipidomics Shared Resource (Developing Core), supported, in part, with funding from National Institutes of Health National Cancer Institute Cancer Center Support Grant P30 CA016059 as well as a Shared Resource Grant S10RR031535 (C.E.C.) from the National Institutes of Health.
• Keywords: wound healing; ceramide-1-phosphate; lipidomics
• Research Categories: Health Sciences, Oncology; Health Sciences, General

Abstract

In these studies, the role of ceramide-1-phosphate (C1P) in the wound-healing process was investigated. Specifically, fibroblasts isolated from mice with the known anabolic enzyme for C1P, ceramide kinase (CERK), ablated (CERK−/− mice) and their wild-type littermates (CERK+/+) were subjected to in vitro wound-healing assays. Simulation of mechanical trauma of a wound by scratching a monolayer of fibroblasts from CERK+/+ mice demonstrated steadily increasing levels of arachidonic acid in a time-dependent manner in stark contrast to CERK−/− fibroblasts. This observed difference was reflected in scratch-induced eicosanoid levels. Similar, but somewhat less intense, changes were observed in a more complex system utilizing skin biopsies obtained from CERK-null mice. Importantly, C1P levels increased during the early stages of human wound healing correlating with the transition from the inflammatory stage to the peak of the fibroplasia stage (e.g., proliferation and migration of fibroblasts). Finally, the loss of proper eicosanoid response translated into an abnormal migration pattern for the fibroblasts isolated from CERK−/−. As the proper migration of fibroblasts is one of the necessary steps of wound healing, these studies demonstrate a novel requirement for the CERK-derived C1P in the proper healing response of wounds.