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In brief

The AMD1 protein helps shift the ratio of gene-regulating polyamines, controlling how rapidly cells multiply across different skin layers.

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Striking a balance in healthy skin

8 Dec 2022

Fine-tuning the levels of three skin cell metabolites could be the key to unlocking treatments for psoriasis and ageing skin.

Handstands are the ultimate test of balance—even the slightest weight shift can topple the pose. Similarly, healthy skin involves a delicate balance of cell renewal and cell death. As skin cells gradually move from the inner to outer layers of our skin, they divide, differentiate into hardy forms, and eventually die to form our body’s protective barrier against the elements.

However, in skin disease such as psoriasis, a hyperproliferative disorder, skin cells can multiply up to 10 times faster than usual, often resulting in itchy, scaly and inflamed patches. Researchers studying the skin’s mysteries have uncovered new details about the root of this uncontrolled proliferation: a balancing act between a triad of metabolites known as polyamines.

"Polyamines, putrescine (Put), spermidine (Spd) and spermine (Spm), are a family of metabolites that are essential for normal cellular function in all cells,” explained Leah Vardy, Covering Executive Director at the A*STAR Skin Research Labs (A*SRL). Polyamines, have previously been observed to be decreased in ageing skin and elevated in hyperproliferative skin showing the importance of tight control of their levels.

To better understand the factors affecting this triad of polyamines in our skin, Vardy and colleagues focused on a polyamine regulator protein called adenosylmethionine decarboxylase 1, or AMD1. In particular, the research group was interested in how AMD1 influenced gene expression patterns in skin cells, and how these changes impacted the skin’s overall ability to act as a protective barrier.

First, the researchers took a closer look at patterns of AMD1 expression within the various layers of healthy human skin. They found that the AMD1 protein was least expressed in the deepest or basal layers of the epidermis, where skin cells normally focus on dividing themselves. Moving outwards, however, AMD1 expression gradually increased, peaking in the outermost skin layers where cells were most differentiated. They also found that AMD1 promoted high levels of Spm, a polyamine essential for the cell differentiation process.

Taking these two findings together, the researchers suggested AMD1 helps skin cells shift their behavioral gears—stopping division and starting differentiation—by gradually altering the balance of the three polyamines in different skin layers.

In follow-on cell culture experiments, the team blocked AMD1 activity in differentiating skin cells and found that this threw off the balance between Put, Spm and Spd, resulting in skin cells that behaved much like they would in patients with psoriasis. However, adding Spd and Spm into the culture ‘rescued’ skin cell differentiation, restoring a robust epidermal barrier.

Moving forward, Vardy said the team plans to explore the possibility of using AMD1 as a treatment target to tackle hyperproliferative skin disorders and ageing-related skin conditions.

“Our findings have demonstrated the importance of fine-tuning the levels and ratios of the three polyamines,” Vardy commented, adding that they identified AMD1 as being central to maintaining this equilibrium. “We need a better understanding of how these polyamine ratios change in hyperproliferative conditions, as any therapeutic methods would need to control them to be effective.”

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

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References

Rahim, B.A., Lim, H.K., Tan, C.Y.R., Jia, L., Leo, V.I., et al. The polyamine regulator AMD1 upregulates spermine levels to drive epidermal differentiation. Journal of Investigative Dermatology 141 , 2178-2188 (2021). | article

About the Researcher

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Leah Vardy

Covering Executive Director

A*STAR Skin Research Labs (A*SRL)
Leah Vardy received her PhD at the Imperial Cancer Research Fund in London and did her postdoctoral research with Terry Orr-Weaver at the Whitehead Institute in Cambridge, USA. In 2007, she was appointed to the Institute of Medical Biology where she studied post-transcriptional control in embryonic stem cells. Her current work focuses on understanding the polyamine-dependent control of gene expression in the human epidermis in the context of pigmentation, wound healing, and ageing. She joined the Skin Research Institute of Singapore in April 2018 to continue this line of research and now serves as the covering Executive Director of the A*STAR Skin Research Labs.

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