Hepatoma derived growth factor (HDGF) is released upon injury and contributes to skin repair in an age-dependent manner

Summary: Abstract Body: Connective tissues, including skin and cartilage, utilise several mechanisms to respond to injury. In cartilage, one such mechanism is the release of heparin-bound growth factors (GFs) from the extracellular matrix. These GFs include fibroblast growth factor (FGF)-2 and connective tissue growth factor (CTGF) which are pro-regenerative in both skin and cartilage. Another GF is hepatoma derived growth factor (HDGF), about which little is known. We hypothesized that HDGF, like FGF2 and CTGF, plays a role in tissue injury and repair. Western blots of medium conditioned by either injured skin or cartilage, from both pig and mouse, confirmed the injury-dependent release of HDGF in wild-type (WT) tissues, but not in HDGF-knockout (Hdgf-/-). To explore the function of HDGF in tissue repair in vivo, we studied its role in skin wounding. A 3-day delay in wound healing was observed in 15- and 26-week-old, but not 10-week-old, Hdgf-/- male mice when compared with age-matched WT animals. Granulation tissue was significantly increased in 15-week-old Hdgf-/- males (unpaired two-tailed t-test, p=0.004) compared to WT at 7 days post-wounding. Wounded Hdgf-/- males developed features of dermatitis, not observed in WT animals. To explore the mechanism of action of HDGF, RNA bulk sequencing of WT and Hdgf-/- cartilage was performed. Among the top 50 differentially expressed genes ordered by adjusted p-value, the most striking difference was observed in the expression of ribosomal genes, both before and after cartilage injury. Skin RNA bulk sequencing and labelled proteomic studies in skin are completed and we are awaiting results. While the role of HDGF in injury is yet to be fully realised, this work demonstrates for the first time the injury-induced nature of HDGF release in skin and cartilage and describes its age-dependent role in tissue repair. Anastasia Ardasheva¹, Harry Walton¹, Jadwiga Zarebska¹, Linyi Zhu¹, Tonia Vincent¹ 1. Kennedy Institute of Rheumatology, University of Oxford, Oxford, England, United Kingdom. Stem Cell Biology, Tissue Regeneration and Wound Healing