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Targeting an Ancient Biological Stress Response Could Help Prevent Hair Loss

A man holding a clump of his hair and holding his head
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One of the ways in which cells respond to stressful conditions includes restricting healthy hair growth, according to a new study.

Given that the activation of this cellular response – known as the integrated stress response (ISR) – is linked to a proliferative block in the human hair follicle, researchers from the University of Manchester posit that targeting this pathway to mitigate ISR activation could be used to help maintain hair follicles and treat hair loss.

The study was published in the journal PLOS ONE.

An unexpected discovery

The Manchester Hair Research Group discovered the link between ISR activation and hair growth in an experiment testing a drug to see if it cultivates human scalp hair follicles in a dish.

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“We were testing a drug that targets metabolism in human hair follicles to influence how cells generate energy, which, based on the work of others, we expected to stimulate stem cells,” said Dr. Talveen Purba, research fellow at the University of Manchester and senior author of the study. “However we found the opposite was true: hair growth was instead blocked, as cells, including stem cells, quickly stopped dividing.”

To investigate further, the researchers conducted transcriptomics analysis, which revealed that mitochondrial pyruvate carrier (MPC) inhibition with the drug of interest was shown to promote a gene expression signature indicative of disrupted cell signaling, mitochondrial dysfunction and activation of the ISR.

What is the integrated stress response (ISR)?

The ISR is an ancient biological response that occurs across life forms. It allows cells to halt regular activities by making fewer proteins and entering a partial stasis to adapt and deal with stressful conditions. It is triggered in conditions such as poor nutrient availability, viral infection or when there is a build-up of misshaped proteins in cells. Targeting the ISR is already of interest to scientists studying cancer, neurodegenerative disorders and aging.

Using RNAScope, the researchers confirmed the upregulation of ATF4 – a transcription factor that mediates ISR – and the ATF4-target gene ADM2 on human hair follicle tissue sections in situ.

Moreover, treatment with the ISR inhibitor ISRIB reduced both the upregulation of ADM2 and the proliferative hair growth block imposed via MPC inhibition.

Looking at hair follicles under the microscope, the researchers highlighted the striking consistency in the response between hair follicles from different people.

“This work shows how the human hair follicle, as a highly complex mini-organ, is capable of sensing and dynamically adapting to changes in nutrient availability and redox homeostasis,” the researchers said.

Following on from this research, the authors are hoping that further studying the ISR in the human hair follicle could elucidate novel insights into human hair growth, hair loss disorders, tissue metabolism and aging.

The researchers are hopeful that targeted activation of this pathway could lead to new treatments for individuals with hair loss conditions such as alopecia. However, further work is needed to test the feasibility of blocking ISR activation in the hair follicle since the researchers' ability to achieve this using ISRIB was limited.

Reference: Pye D, Scholey R, Ung S, Dawson M, Shahmalak A, Purba TS. Activation of the integrated stress response in human hair follicles. PLOS ONE. 2024;19(6):e0303742. doi: 10.1371/journal.pone.0303742

This article is a rework of a press release. Material has been edited for length and content.