Researchers Show Hair Loss can be Prevented by Modifying Stem Cell Metabolism

Researchers Show Hair Loss can be Prevented by Modifying Stem Cell Metabolism

Researchers from Cologne and Helsinki have identified a mechanism that prevents hair loss. Hair loss occurs when hair follicle stem cells are exhausted new hair follicles are not produced, leading to permanent hair loss. Normally, in response to environmental damage and ultraviolet radiation, skin cells die, and hair follicles are damaged. The dead skin cells are shed and hairs are lost at a rate of around 500 million skin cells and around 100 hairs a day.

Stem cells differentiate to replace the lost skin cells and damaged hair follicles. Stem cells are highly proliferative and long-lived, but over time the activity and health of the stem cells declines. If daughter cells do not recapture their stemness and do not become stem cells again, they will not be able to generate the outer root sheath of the hair follicle. Once the stem cells are exhausted, hair loss will occur.

The researchers report that the root cause of hair loss is a change in the metabolic state of stem cells. While hair follicle stem cells can tolerate low oxygen levels, their daughter cells are not so metabolically adept. While stem cells rely on glycolysis, the daughter cells rely on oxidative phosphorylation and glutamine metabolism, but in order to prevent hair loss, they must be able to change back to glycolysis.

In their paper, the researchers explain how it is possible to manipulate the metabolic state of stem cells, and by doing so, prevent hair loss. “Hair follicle stem cell (HFSC) fate reversibility and glutamine metabolism are regulated by the mammalian target of rapamycin complex 2 (mTORC2)-Akt signaling axis within the niche,” explained the researchers in their paper. “Deletion of mTORC2 results in a failure to re-establish the HFSC niche, defective hair follicle regeneration, and compromised long-term maintenance of HFSCs.”

The researchers studied the transcriptional and metabolic properties of hair follicle stem cells and their daughter cells. “Intriguingly, these studies showed that stem cells and daughter cells have distinct metabolic characteristics’, said Dr. Christine Kim, co-lead author of the study. ‘Our analyses further predicted that Rictor, an important but relatively poorly understood molecular component of the metabolic master regulator mTOR pathway, would be involved.’

Further analyses revealed the depletion of stem cells was due to the loss of metabolic flexibility. When the regenerative cycle ends and new hair is made, stem cells return to their specific location and go back to a quiescent state.

“The key finding of this study is that this so-called fate reversibility requires a shift from glutamine metabolism and cellular respiration to glycolysis,” said Xiaolei Ding, PhD, of the department of dermatology, University of Cologne and co-lead author of the study. “The stem cells reside in an environment with low oxygen availability and thus use glucose rather than glutamine as a carbon source for energy and protein synthesis.” The metabolic change is due to the low oxygen concentration and Rictor signaling.

The researchers found that mice lacking Rictor signaling had significantly delayed hair follicle regeneration and cycling, which suggested impaired stem cell regulation. As the mice aged, they exhibited hair loss and a reduction in the number of stem cells.

“The application of a glutaminase inhibitor was able to restore stem cell function in the Rictor-deficient mice, proving the principle that modifying metabolic pathways could be a powerful way to boost the regenerative capacity of our tissues,” said Sabine Eming, MD, PhD, Univrsity of Cologne and senior author. The researchers now need to investigate how the findings of their study may translate to stem cell biology in humans, and whether it could be possible to preserve the regenerative capacity of stem cells to protect the hair follicle from aging, and thus prevent hair loss.

You can read more about the study in the paper – Glutamine Metabolism Controls Stem Cell Fate Reversibility and Long-Term Maintenance in the Hair Follicle – which was recently published in the journal Cell Metabolism. DOI: 10.1016/j.cmet.2020.08.011

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