Papa

The hair follicle is ideal for investigating stem cell regulation. This study has implications for wound healing, cancer, and hair growth. Activation of the ISR in HFSCs regulates cell fate decisions, promoting the epidermal fate over the hair follicle fate.🧵 

When skin is wounded, the ISR is activated to promote re-epithelialization at the expense of hair growth. Serine deprivation potentiates the response, even activating the ISR in non-wounded skin. Ser deprivation may speed wound healing, while ISR inhibition might treat hair loss.

It's more relevant to scarring alopecias than AGA. The ISR might have a small role in AGA, but activated by an alternative pathway, such as PERK, downstream of ER stress, and independent of nutritional deficiency. There's an AGA SNP in an enhancer near LHX2 that might disrupt...

...a binding site for ISR-activated ATF3. It slightly increases the odds of severe baldness. ATF3 might even protect against AGA by repressing LHX2, which would upregulate the Wnt targets LGR5 and LEF1 in the hair germ.

They did not cure baldness. They did something that isn't mechanistically relevant to common pattern hair loss. By promoting glycolytic metabolism they are able to activate stem cells in the follicular bulge, but hair loss is not caused by failure of these stem cells to activate 

Rather it’s caused by failure of progenitors to proliferate and differentiate into TACs that go on to produce the hair shaft. While PP405 activates stem cells, like dozens of other compounds, it doesn't contribute to the differentiation pathway. Differentiation is regulated by

inductive Wnt signals from dermal papilla cells. DHT causes the dysfunction and progressive depletion of DP cells. Stem cells continue to be activated into late stage baldness, albeit with greater latency, but they will fail to differentiate w/o Wnt signals secreted by the DP

Continued activation is also evidenced by progressive enlargement of the sebaceous gland which is derived from the same bulge stem cell population. As the progenitor pool shrinks, the hair shaft gets smaller. For the pool to expand, Wnt signals secreted from the DP are required

The smaller the DP becomes the less the progenitor pool expands, resulting in a smaller hair. It’s evident that PP405 promotes anagen entry but won't reverse miniaturization because it will only activate progenitor cells to the extent of expansion that the dermal papilla supports

With a depleted DP that means you’ll get more hairs in the active growth phase, but they will remain miniaturized. Rapamycin has the same effect as PP405, and there are vendors selling topical rapamycin creams for hair loss. If it cured hair loss the internet would know by now.

Propranolol also does it, but there have been no case reports of hair growth. Cyclosporine, PBM, prolactin receptor antagonists, and norepinephrine all activate bulge stem cells. JAK inhibitors too. They were trialed for pattern hair loss but abandoned due to minimal efficacy