In brief

While a protein called LRG1 is essential for wound healing, too much LRG1 can also hinder the process by overstimulating the immune system.

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Deciphering a wound healing paradox

4 Jun 2021

A*STAR researchers identify a novel mechanism in which an inflammatory protein heals wounds in healthy individuals but has the opposite effect in diabetics.

Time heals all wounds. Unfortunately, the saying doesn’t always apply to people living with diabetes. Around a quarter of them suffer from chronic non-healing wounds, a debilitating condition that can result in infections, amputations and, in serious cases, even death.

In healthy people, cuts and grazes normally heal through a sequence of events starting with the inflammatory phase, where immune cells flood into the wound to prevent infection. At the final remodeling phase, skin tissue regenerates and a scar is formed. In diabetics, these processes are often disrupted or delayed, leading to chronic wounds.

In particular, an inflammatory protein called LRG1 is known to be linked to wound healing, albeit in paradoxical ways. On the one hand, LRG1 levels are elevated in patients with diabetic foot ulcers, but it was also shown to be required for timely wound closure in lab animals. To resolve this conflict, a team led by Xiaomeng Wang and Wanjin Hong from A*STAR’s Institute of Molecular and Cell Biology (IMCB) studied mice genetically engineered to lack LRG1.

They found that a lack of LRG1 in otherwise healthy mice led to reduced immune cell infiltration and delayed wound healing. In surprising contrast, removing LRG1 was found to have the opposite effect in diabetic mice, accelerating wound healing.

These seemingly paradoxical findings can be explained by the complex role that LRG1 plays at different stages of the wound healing process, said Wang, who is also an Associate Professor at Duke-NUS Medical School.

“LRG1 is required for normal immune cell function, new blood vessel formation, as well as epithelial cell migration and proliferation, all of which are critical for timely wound closure,” she explained. “However, too much LRG1 promotes the formation of neutrophil extracellular traps (NETs), which lead to chronic inflammation and delayed wound closure.”

NETs are typically secreted during the inflammatory phase of wound healing to eliminate pathogens. Too much LRG1, however, triggers an imbalance: NETs accumulate causing wound healing to stall at the inflammatory phase.

A similar mechanism may be occurring in humans, say the authors, since high LRG1 levels are observed in diabetic patients with chronic foot ulcers. These findings highlight an exciting clinical possibility that the team is currently exploring treatments targeting LRG1 to dampen inflammation and kickstart the wound healing process.

“In collaboration with A*STAR’s Experimental Drug Development Centre (EDDC), we are developing LRG1-neutralizing antibodies,” said Wang. “We will evaluate the therapeutic potential of LRG1-neutralizing antibodies and see whether they could promote wound closure in diabetic mice.”

The A*STAR-affiliated researchers contributing to this research are from the Institute of Molecular and Cell Biology (IMCB).

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Liu, C., Teo, M.H.Y., Pek, S.L.T., Wu, X., Leong, M.L., et al. A Multifunctional Role of Leucine-Rich α-2-Glycoprotein 1 in Cutaneous Wound Healing Under Normal and Diabetic Conditions. Diabetes 69, 2467–2480 (2020) | article

About the Researcher

Xiaomeng Wang obtained her BSc from Beijing Normal University, China, and her PhD from Newcastle University, UK. Following a post-doctoral fellowship at Manchester University, UK, she continued her scientific career at University College London, UK. In 2013, she moved to Singapore where she currently holds a joint appointment as Principal Investigator at A*STAR’s Institute of Molecular and Cell Biology (IMCB) and Associate Professor at Duke-NUS Medical School.

This article was made for A*STAR Research by Wildtype Media Group