Coordinated hedgehog signaling induces new hair follicles in adult skin.

Elife. 2020 Mar 17;9. pii: e46756. doi: 10.7554/eLife.46756.
Coordinated hedgehog signaling induces new hair follicles in adult skin.
Sun X#1, Are A#1, Annusver K#1, Sivan U#1, Jacob T1, Dalessandri T1, Joost S1, Füllgrabe A1, Gerling M1, Kasper M1.

Hair follicle (HF) development is orchestrated by coordinated signals from adjacent epithelial and mesenchymal cells. In humans this process only occurs during embryogenesis and viable strategies to induce new HFs in adult skin are lacking. Here, we reveal that activation of Hedgehog (Hh) signaling in adjacent epithelial and stromal cells induces new HFs in adult, unwounded dorsal mouse skin. Formation of de novo HFs recapitulated embryonic HF development, and mature follicles produced hair co-occurring with epithelial tumors. In contrast, Hh-pathway activation in epithelial or stromal cells alone resulted in tumor formation or stromal cell condensation respectively, without induction of new HFs. Provocatively, adjacent epithelial-stromal Hh-pathway activation induced de novo HFs also in hairless paw skin, divorced from confounding effects of pre-existing niche signals in haired skin. Altogether, cell-type-specific modulation of a single pathway is sufficient to reactivate embryonic programs in adult tissues, thereby inducing complex epithelial structures even without wounding.

PLAIN-LANGUAGE-SUMMARY:
We are born with all the hair follicles that we will ever have in our life. These structures are maintained by different types of cells (such as keratinocytes and fibroblasts) that work together to create hair. Follicles form in the embryo thanks to complex molecular signals, which include a molecular cascade known as the Hedgehog signaling pathway. After birth however, these molecular signals are shut down to avoid conflicting messages – inappropriate activation of Hedgehog signaling in adult skin, for instance, leads to tumors. This means that our skin loses the ability to make new hair follicles, and if skin is severely damaged it cannot regrow hair or produce the associated sebaceous glands that keep skin moisturized. Being able to create new hair follicles in adult skin would be both functionally and aesthetically beneficial for patients in need, for example, burn victims. Overall, it would also help to understand if and how it is possible to reactivate developmental programs after birth. To investigate this question, Sun, Are et al. triggered Hedgehog signaling in the skin cells of genetically modified mice; this was done either in keratinocytes, in fibroblasts, or in both types of cells. The experiments showed that Hedgehog signaling could produce new hair follicles, but only when activated in keratinocytes and fibroblasts together. The process took several weeks, mirrored normal hair follicle development and resulted in new hair shafts. The follicles grew on both the back of mice, where hair normally occurs, and even in paw areas that are usually hairless. Not unexpectedly the new hair follicles were accompanied with skin tumors. But, promisingly, treatment with Hedgehog-pathway inhibitor Vismodegib restricted tumor growth while keeping the new follicles intact. This suggests that future work on improving “when and where” Hedgehog signaling is activated may allow the formation of new follicles in adult skin with fewer adverse effects.

Full Study:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7077985/

I have found some natural SHH inducers:

Thuja Orientalis Extract (Hair growth-promoting activity of hot water extract of Thuja orientalis.)
EGCG (Epigallocatechin-3-Gallate Promotes the Growth of Mink Hair Follicles Through Sonic Hedgehog and Protein Kinase B Signaling Pathways.)
Chitosan (Hair growth-promoting activities of chitosan and surface-deacetylated chitin nanofibers.)
Polygonum multiflorum extract (Topical application of Polygonum multiflorum extract induces hair growth of resting hair follicles through upregulating Shh and β-catenin expression in C57BL/6 mice.)
Red Ginseng Oil (Hair Regenerative Mechanisms of Red Ginseng Oil and Its Major Components in the Testosterone-Induced Delay of Anagen Entry in C57BL/6 Mice.)

It seems that vitamin D3 also plays a role.