In brief

Researchers discovered reduced cell division capacities, gene expression alterations and elevated inflammatory signatures in wound macrophages from older mice that can contribute to disruptions in healing.

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Dysfunctional immune cells stall wound healing

24 Aug 2023

New insights into the age-associated changes affecting macrophages offer promising avenues for the treatment of chronic wounds.

Macrophages are the immune soldiers deployed to destroy nasty pathogens that try to gain access through breaches in the skin barrier. These powerful cells aren’t just fighters but also healers, secreting a cocktail of anti-inflammatory chemicals to help promote wound healing.

But as people age, their wounds don’t heal as quickly, leaving scientists to suspect that macrophages may be losing their edge.

“Cutaneous wounds in the elderly tend to be slow healing with altered wound closure dynamics and changes in tissue integrity,” said Chin Yan Lim, an Adjunct Principal Investigator at the A*STAR Skin Research Labs (A*SRL).

Lim explained that we still don’t fully understand how ageing can impact macrophage (and other skin cell) activity during wound healing—a gap that’s resulted in the limited availability of targeted treatments for chronic wounds in older adults.

Lim’s team at A*SRL forged a partnership with researchers from the University of Manchester and first author Christabel Dube, a joint PhD student funded under the A*STAR Research Attachment Programme (ARAP), to get to the bottom of this question by comparing wound healing dynamics in young and aged mice.

“We focused on understanding a specific stage of wound healing, the early-mid inflammation phase, to systematically probe the effect of ageing on cellular response to excisional injury,” explained Lim.

To achieve this, the team employed advanced techniques such as high-parameter flow cytometry and functional transcriptomic analyses, which together, provided valuable insights on the functional and genetic alterations as macrophages age.

In their study, they described how there were fewer macrophages in the wounds of older mice compared to younger mice at around a week post-injury. The researchers discovered that the macrophages in aged wounds had lower activity in genes related to cell division, DNA repair and other processes important for healing while producing higher levels of pro-inflammatory molecules. This resulted in an extended early-mid inflammation phase, creating slow-to-heal wounds.

This is a much-needed glimpse into the complex cellular and genetic changes behind chronic, non-healing wounds in older individuals.

“By targeting and dampening the hyperinflammatory signature in the aged macrophages, we may shorten the inflammation phase to progress to the next stage of wound healing without delay,” Lim said, adding that this strategy can help accelerate wound repair in aged populations.

Wound healing is a multi-dimensional process that requires the coordinated activity of many different skin cell types, which is the focus of the group’s continued research efforts. Lim and colleagues are probing other skin cell types using single-cell RNA sequencing to uncover more mechanisms contributing to sluggish wound healing in aged skin.

The A*STAR-affiliated researchers contributing to this research are from the A*STAR Skin Research Labs (A*SRL).

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Dube, C.T., Ong, Y.H.B., Wemyss, K., Krishnan, S., Tan, T.J., et al. Age-related alterations in macrophage distribution and function are associated with delayed cutaneous wound healing. Frontiers in Immunology 13, 943159 (2022). | article

About the Researcher

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Chin Yan Lim

Adjunct Principal Investigator

A*STAR Skin Research Labs (A*SRL)
Chin Yan Lim is presently an Adjunct Principal Investigator at the A*STAR Skin Research Labs (A*SRL). She obtained her BSc (First Class), with a double major in Biochemistry and Microbiology at the National University of Singapore and her PhD in Molecular Biology at the University of California, San Diego with James T. Kadonaga. She developed a deep interest in understanding epigenetic mechanisms that impact cell fate decisions during two postdoctoral stints at the Genome Institute of Singapore and the Institute of Medical Biology, A*STAR. She is also an Adjunct Assistant Professor at NUS, Yong Loo Lin School of Medicine, and Head of Genetic Strategies at Hummingbird Bioscience Pte Ltd. Her lab studies the impact of chromatin structure alterations in the context of skin development, stem cells, cancer and ageing.

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