Topical application of protein accelerates wound healing in a diabetic mouse model

Written by Alexandra Thompson

Researchers from the NIH (Bethesda, MD, USA) have discovered that the protein-folding gene Hsp60 plays a critical role in tissue regeneration and wound healing through immune signaling, and have furthermore demonstrated that topical application of a HSP60-containing gel dramatically accelerates skin wound closure in a diabetic mouse model.

Investigators from the NIH (Bethesda, MD, USA) have identified an essential gene for wound healing following a systematic genetic screen in zebrafish, and moreover demonstrated that topical application of HSP60 to a diabetic mouse skin wound model dramatically accelerated wound healing.

Zebrafish are commonly used for research into wound healing and regenerative medicine thanks to their native regenerative abilities that allow them to regrow tissues, such as heart tissue, that do not regrow well in other organisms. In order to identify new components involved in the wound healing process, researchers from the NIH performed a systematic screen to identify genes essential for hair cell regeneration in zebrafish, and identified Hsp60 as being critical.

Next, the team from the National Human Genome Research Institute (NHGRI), the National Eye Institute (NEI) and colleagues demonstrated that the protein injected extracellularly into zebrafish promoted cell proliferation and regeneration in both hair cells and caudal fins. The team next applied HSP60 to a diabetic mouse skin wound model in a gel, and found that it dramatically accelerated wound healing compared with controls: complete healing of a puncture wound after only 21 days.

The team sought to elucidate the mechanism behind this improved response, and found that HSP60 is released at the site of injury and triggers a specific induction of M2 phase CD163-positive monocytes, meaning that HSP60 has an extracellular signaling function in injury inflammation and tissue regeneration beyond its normal intracellular role in protein folding, likely through promoting the M2 phase for macrophages.

“When we injected Hsp60 directly to the site of injury, the tissue surrounding the wound started to regenerate faster,” author Dr Shawn M Burgess explained. “That’s when we got really excited.”

By helping to better understand the genetics and mechanisms behind regeneration and wound healing, the findings could help the development of novel therapies for speeding up wound healing in chronic wounds such as diabetic ulcers (diabetes being the leading causes of non-traumatic lower limb amputations in the USA), as well as acute or normal wounds: for example, it is possible that other heat shock proteins may play a similar role.

They also hope that the topical treatment will act the same way in humans as it did in the mouse model, and furthermore wish to investigate whether it would accelerate repair in any wound rather than just diabetic wounds.

Sources: Pei W, Tanaka K, Huang SC et al. Extracellular HSP60 triggers tissue regeneration and wound healing by regulating inflammation and cell proliferation. npj Regenerative Medicine doi:10.1038/npjregenmed.2016.13 (2016) (Epub ahead of print);