The role of hepatoma derived growth factor in tissue injury and repair

Thesis

Connective tissues, including skin and cartilage, utilise several mechanisms to respond to injury. In cartilage, one such mechanism is through the release of heparin-bound growth factors from the extracellular matrix. These include fibroblast growth factor (FGF)-2 and connective tissue growth factor (CTGF) which are pro-regenerative in both skin and cartilage. Another growth factor is hepatoma derived growth factor (HDGF), about which little is known. We hypothesised that HDGF, like FGF2 and CTGF, plays a role in tissue injury and repair.

Medium conditioned by injured skin and cartilage (pig and mouse) confirmed an injury-dependent release of HDGF protein in normal wild-type (WT) tissues, but not in HDGF-knockout (Hdgf-/- ). Bulk RNA sequencing analysis showed similar responses to injury at 4 hours in WT and Hdgf-/- cartilage. Five genes, including Hdgf itself, were differentially expressed at baseline in both skin and cartilage. Three of these were genes encoding ribosomal subunits leading to further investigation of HDGF’s role in protein translation. Ex vivo SILAC labelling of newly synthesised proteins in injured skin (at 48 hours) revealed a global decrease in protein synthesis in Hdgf-/- tissue as well as a strong reduction in proteins involved in translation.

In vivo, murine, studies revealed a delay in skin wound healing in 15- and 26-week-old, but not 10-week-old, Hdgf-/- male mice when compared with agematched WT animals. Histological analysis of wounds confirmed features of delayed healing (delayed re-epithelialization and increased granulation tissue) in 15-week-old Hdgf-/- males. This work demonstrates for the first time the injury induced nature of HDGF release in skin and cartilage and its role in skin repair. The mechanism for HDGF’s effects after tissue injury does not appear to be through early transcriptional regulation, but through control of protein translation.

Authors: Ardasheva, A

• DOI: 10.5287/ora-9rvdqyme5
• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford
• Language: English