Anterior gradient 2 is induced in cutaneous wound and promotes wound healing through its adhesion domain

• Published in: The FEBS journal Vol. 284; no. 17; pp. 2856 - 2869
• Main Authors: Zhu, Qi, Mangukiya, Hitesh Bhagavanbhai, Mashausi, Dhahiri Saidi, Guo, Hao, Negi, Hema, Merugu, Siva Bharath, Wu, Zhenghua, Li, Dawei
• Format: Journal Article
• Language: English
• Published: England Blackwell Publishing Ltd 01.09.2017
• Subjects: Adhesion; Angiogenesis; Animals; anterior gradient 2; cell migration; Cell Movement; Cells, Cultured; Cytoplasm; Epidermis; Epidermis - metabolism; Epidermis - pathology; Epidermis - physiopathology; Extracellular matrix; Fibroblasts; Fibroblasts - physiology; Human Umbilical Vein Endothelial Cells - physiology; In vitro methods and tests; Keratinocytes; Keratinocytes - physiology; Male; Mammals; MAP Kinase Signaling System; Mice, Inbred BALB C; Mucoproteins - genetics; Mucoproteins - metabolism; Protein disulfide-isomerase; Protein Domains; Regeneration; Skin; Tongue; Topical application; Transcriptional Activation; Wound Healing; Zebrafish; cell migration; fibroblasts; wound healing; anterior gradient 2; keratinocytes
• ISSN: 1742-464X; 1742-4658
• DOI: 10.1111/febs.14155

Anterior gradient 2 (AGR2), a member of protein disulfide isomerase (PDI) family, is both located in cytoplasm and secreted into extracellular matrix. The orthologs of AGR2 have been linked to limb regeneration in newt and wound healing in zebrafish. In mammals, AGR2 influences multiple cell signaling pathways in tumor formation and in normal cell functions related to new tissue formation like angiogenesis. However, the function of AGR2 in mammalian wound healing remains unknown. This study aimed to investigate AGR2 expression and its function during skin wound healing and the possible application of external AGR2 in cutaneous wound to accelerate the healing process. Our results showed that AGR2 expression was induced in the migrating epidermal tongue and hyperplastic epidermis after skin excision. Topical application of recombinant AGR2 significantly accelerated wound‐healing process by increasing the migration of keratinocytes (Kera.) and the recruitment of fibroblasts (Fibro.) near the wounded area. External AGR2 also promoted the migration of Kera. and Fibro. in vitro in a dose‐dependent manner. The adhesion domain of AGR2 was required for the formation of focal adhesions in migrating Fibro., leading to the directional migration along AGR2 gradient. These results indicate that recombinant AGR2 accelerates skin wound healing through regulation of Kera. and Fibro. migration, thus demonstrating its potential utility as an alternative strategy of the therapeutics to accelerate the healing of acute or chronic skin wounds. Anterior gradient 2 (AGR2), induced in the migrating epidermal tongue and hyperplastic epidermis after skin excision, plays an important role in cutaneous wound healing. Topical application of AGR2 promotes wound healing by increasing migration of keratinocytes and recruitment of fibroblasts (Fibro.). The adhesion domain of AGR2 is required for the formation of focal adhesions, which leads Fibro. directional migration along AGR2 gradient.