On the Arrector Pili

Jumpman explains the arrector pilli’s relevance to healthy hair follicle functioning The arrector pili muscle (APM) promotes growth via sympathetic nerve connection, transmitting norepinephrine and, in turn, activating Beta-2 adrenergic receptors in the hair bulge. The downstream activity of these receptors inhibits FOXP1 and FGF18, as well as promoting cell-cycle related genes. The arrector pili is maintained by Sonic hedgehog (Shh) emitted from Transit Amplifying Cells (TACs)--progenitor cells in the hair matrix that also maintain the dermal papilla

After Shh is downregulated over a prolonged period, the arrector pili muscle is lost. Jumpman doesn’t think the APM is necessary to re-enter anagen, but believes we can still obtain the benefits of the APM through Beta-2 agonists, such as procaterol. It remains to be seen how effective Beta-2 agonists are as a treatment, although they are hypothesized to work through the GPCR-cAMP-CREB pathway

Contributors: Jumpman

Convhairsations

Synthetic Pug’s Theory of Balding: Synthetic Pug argues that TGFb downregulates SOD2, inducing senescence in dermal papilla cells (DPCs). In a positive feedback loop, senescent cells emit SASP factors, which cause TGFb upregulation, which increases SASP factor production, and the cycle continues. The compounding effects of TGFb is why hair loss is progressive and not immediate, but still tends to happen in one hair cycle. Higher expression of AR may also play a role, as higher expression leads to more Dkk1, which inhibits Wnt, but it doesn’t appear to be causative.

Herber t ’s Theory of Balding: Herber t believes that at least one co-activator in the androgen receptor pathway experiences expression changes.

Metabobbly’s Theory of balding: Metabobbly believes there is shor tage of acetyl-CoA, which causes the RNA II polymerase complex to be terminated most likely by a HDAC. As such, longer genes are no longer expressed and cells eventually become senescent.

Ndimension’s Theory of Balding: Ndimension argues that our hair stem cells have a set number of cycles based on our genetics and epigenetics.

Jumpman’s Theory of Balding: Jumpman illustrates how PAI-1 and Twist-1 modify FGFR signaling to downregulate R-spondins and Wnt-signaling.

On Models: Jack Scannell advised us to look at Markhov models, due to the flux state of hair loss–both phenotypically as our hair transitions from anagen to catagen to telogen, and microscopically as some of our dermal papilla move to the dermal sheath in late anagen and return in late telogen.

On ALK5: Jumpman repor ts that methylation of cer tain genes cause TGFb to signal more to ALK5 than ALK1 ALK5 knockouts have been shown to reduce TGFb-induced growth inhibition of outer root sheath (ORS) stem cells

On Microneedling: The best microneedling technique, according to Follica, is 0.8mm deep every two weeks. Jumpman writes, “People got this idea in their head that deeper is better, but density>depth.” Microneedling’s mechanism of action is believed to be from increased Wnt proteins and HGF receptor expression.

Natural 5ar Inhibitors: Molotov Ribbentrot identifies a naturally derived AR inhibitor from mangrove trees. Macaque shares Fenubreek as a natural 5-ar inhibitor, recommended by Nick Sangrove–rumor has it can drop DHT by 10%. Andrew Huberman tells us how he just couldn’t stand the side effects of DHT inhibition in circumin. Just imagine if he tried Finasteride–Herber t shares his analysis of the molecule Salugi states that better delivery vehicle is better than nutraceuticals, although it would be nice to know for sure if natural 5ar inhibitors are hope or cope.

TGFb and Reactive Oxygen Species: Herber t, Synthetic Pug, and Ghter question the chicken and egg problem of TGFb and reactive oxygen species (ROS). Which comes first?

C3A and Procyanidin: Herber t and Synthetic Pug continues to push forward C3A, which they believe likely has the same mechanism of action as procyanidin but in stronger amplitude. If we can get a clinical dose of C3A in scalp skin, we can hypothetically scavenge ROS and reduce TGFb. Synthetic Pug points out, however, that high amounts of antioxidants can lead to other health problems. siRNA Treatments: If Herber t could design a drug, it would be a nano-formulated siRNA that is able to keep the iRNA in the par ticle in the skin, but then releases the par ticle once it hits blood, leading to degradation. Jumpman ideated a Twist-1 siRNA knock-out, which would pair very nicely with Herber t’s model.

Jumpman on Alopecia Areata: If you are like andy1 and have a genetic predisposition to alopecia areata, Jumpman advises to not take JAK inhibitors as a prophylactic. Most people who are predisposed to alopecia areata will never actually develop it.

JWPharma and YAP: Jumpman repor ts that JWPharma was granted its first oversees patent for its GDNF activator. GDNF upregulates YAP signaling, the same pathway that Ver teporfin suppresses for its scar prevention treatment. Jumpman, Endana, Tigris, and Ghter debated whether we want to upregulate or downregulate YAP. Tigris provided studies of YAP’s upregulation in tissue regeneration, while Jumpman countered with YAP silencing’s ability to upregulate TRPS1 and RSPO1 in wound healing–two desirable growth genes.

DMSO At Home: Visangle and Jumpman repor t that placebo groups that use 100% dimethylsulfoxide (DMSO) tend to grow hair. The compound is less toxic than ethanol, if you’re conducting at-home research.

NMR Verification: Verifying a compound’s structure at home? Using an NMR spectrometer could be helpful. Benjels and Jumpman tackle TM's structure.

On Anagen: Herber t repor ts that the hair follicle is not fixed during anagen. Synthetic Pug argues that prolonging anagen may not change hair miniaturization, if it doesn’t also solve for senescence. Pug claims anagen prolongation may regrow hair in areas with viable DPC amounts, but follicles with too many senescent DPCs would not return from a vellus state. Pug’s theory may explain why HMI-115 may not regrow hair in fully bald areas. He also poses an interesting study idea: can we quantify the amount of miniaturization reversal, if we know the percentage of anagen prolongation?

Dynamic Melanocytes: Melanocytes are a dynamic stem cell group, constantly differentiating and moving between the hair bulge and germ. Jumpman teaches that if the colorful cell group returns to the germ, they should be able to differentiate normally If they become stuck in the bulge, the patient will experience hair graying, and potentially hair loss in some, as senescent melanocytes may signal SASP to adjacent hair cell groups.

Minoxidil’s Mechanism: In Hair Cuts #2, we repor ted that “Alongside angiogenesis, Jumpman pointed out that Minoxidil inhibits GSK3b and SFRP1, upregulates LHX2, and promotes keratinocyte differentiation - mostly mediated through the upregulation of Hepatocyte Growth Factor (HGF), an executor pathway outlined by Ralf as good for hair growth.” This month, Synthetic Pug supplemented our minoxidil research with more fuel. Minoxidil acts on DPCs to stimulate VEGF and may also upregulate androgen metabolism through 17b-hydroxysteroid dehydrogenase upregulation Herber t hypothesizes that the drug may be countering oxidative stress-induced senescence from androgens.

Patient Por tal Data: Herber t wants to analyze genomes from patients who have experienced side effects from finasteride even in microdoses. He also wants to see data from researchers trying RU58841 and CosmeRNA.

Market Briefing: Visangle provides a market overview of hair loss star t-ups, as well as a warning to beware of fake papers Up to 34% of neuroscience papers and 24% of medical papers published in 2020 were probably fake.