P186 Defining a new role for hepatoma-derived growth factor in tissue injury and repair

Abstract

Connective tissues such as skin and cartilage respond to injury in different ways. In cartilage, injury triggers the release of growth factors that activate local repair processes. One such factor, hepatoma-derived growth factor (HDGF), was recently identified by our group and remains poorly characterized. We aimed to study the role of HDGF in connective tissue injury and repair. Release of HDGF from injured skin and cartilage of wildtype (WT) and HDGF-knockout (Hdgf−/−) mice was examined by Western blot. Bulk RNA sequencing was performed in WT and Hdgf−/− tissues, and protein turnover was measured in SILAC-labelled skin biopsies from WT and Hdgf−/− animals via mass spectrometry. In vivo skin wounding was done in WT and Hdgf−/− male mice aged 10, 15 and 26 weeks. Spatial transcriptomics using the CosMx 1k panel was performed on unwounded skin and at days 3, 5, 7 and 10 postwounding in 15-week-old WT and Hdgf−/− male mice. HDGF was released from injured WT skin and cartilage, but not from Hdgf−/− tissues. Comparison of WT and Hdgf−/− skin and cartilage identified five consistently differentially expressed genes, three of which encoded ribosomal components. Proteomic analysis revealed decreased protein synthesis in injured Hdgf−/− skin. Wound healing was delayed in Hdgf−/− male mice compared with age-matched WT controls, characterized by increased granulation tissue and delayed re-epithelialization. This was observed in 15- and 26-week-old, but not 10-week-old, Hdgf−/− male mice. Spatial transcriptomics analysis of unwounded skin identified gene clusters related to innate immunity, inflammation, basal epithelium and stress response as being less prominent in Hdgf−/− mice. In wounded skin, temporal clustering patterns > 10 days after wounding were consistent with a delayed inflammatory response in Hdgf−/−. Our study demonstrates, for the first time, that release of HDGF following injury from multiple connective tissues has a role in repair, possibly by controlling protein synthesis and modulating infiltrating immune cells.