Extracellular HSP60 triggers tissue regeneration and wound healing by regulating inflammation and cell proliferation

After injury, zebrafish can restore many tissues that do not regenerate well in mammals, making it a useful vertebrate model for studying regenerative biology. We performed a systematic screen to identify genes essential for hair cell regeneration in zebrafish, and found that the heat shock protein Hspd1 (Hsp60) has a critical role in the regeneration of hair cells and amputated caudal fins. We showed HSP60-injected extracellularly promoted cell proliferation and regeneration in both hair cells and caudal fins. We showed that hspd1 mutant was deficient in leukocyte infiltration at the site of injury. Topical application of HSP60 in a diabetic mouse skin wound model dramatically accelerated wound healing compared with controls. Stimulation of human peripheral blood mononuclear cells with HSP60 triggered a specific induction of M2 phase CD163-positive monocytes. Our results demonstrate that the normally intracellular chaperonin HSP60 has an extracellular signalling function in injury inflammation and tissue regeneration, likely through promoting the M2 phase for macrophages. Understanding a tissue-regenerating protein in zebrafish may lead to drugs that can restore wound healing in diabetes patients. Shawn Burgess from the National Human Genome Research Institute in the US and colleagues found that mutant zebrafish deficient in the gene coding for heat shock protein Hspd1 (HSP60) had severely impaired regeneration of fins and of hair cells responsible for detection of movement and vibration. Zebrafish are highly regenerative, normally able to regrow injured tissues. Extracellular injection of HSP60 promoted regeneration of fins and hair cells in the fish, while topical application of the protein on skin wounds in diabetic mice (who typically have wound healing problems) dramatically accelerated wound healing compared to controls. The team found HSP60 is released at injury sites, attracting immune cells, and then signals the resolution of inflammation and promotes cell division and regeneration in surrounding tissues.