A new take on norrin

PARIS & DURHAM, N.C.—Androgen and testosterone have both been examined at length for their role in hair growth—or the lack thereof—but now a new factor is being considered. It’s not a hormone, but a protein: norrin. Research out of France has highlighted how norrin interacts with hair follicles and its role in hair growth.

The key target of interest in this work was dermal papilla cells, which are found at the roots of hair follicles. As noted in a 2011 Journal of Cell Science article, this cell type “not only regulates hair follicle development and growth, but is also thought to be a reservoir of multi-potent stem cells.” It is believed that to some extent, that control results from cell-to-cell communication via extracellular vesicles secreted by surrounding skin cells.

As explained in a 2018 Nature Reviews Molecular Cell Biology article, “Extracellular vesicles are a heterogeneous group of cell-derived membranous structures comprising exosomes and microvesicles, which originate from the endosomal system or which are shed from the plasma membrane, respectively. They are present in biological fluids and are involved in multiple physiological and pathological processes. Extracellular vesicles are now considered as an additional mechanism for intercellular communication, allowing cells to exchange proteins, lipids and genetic material.”

Within the context of hair, research has shown that extracellular vesicles from dermal papilla cells can stimulate the proliferation and migration of follicular keratinocytes, which establish connections with nerves in the skin.

To further explore this, a research team headed up by Dr. Daniel Aberdam of INSERM and the Université de Paris examined exactly how extracellular vesicles (EV) are involved in activating dermal papilla cells. Their results were published in STEM CELLS in an article titled “Extracellular vesicles from activated dermal fibroblasts stimulate hair follicle growth through dermal papilla-secreted norrin.”

“We found that these EVs (st‐EVs) enhanced HF [hair follicle] growth ex vivo. Comparative transcriptomic analysis on DPCs [dermal papilla cells] identified specific activation of the NDP gene, encoding the non‐Wnt ligand Norrin. We found that Norrin was secreted by st‐EVs‐stimulated DPCs activating in a noncell autonomous manner β‐catenin pathway in follicular keratinocytes (human HF keratinocyte [HHFK]) and hair growth ex vivo,” the authors explained in their paper.

When dermal fibroblasts secrete certain extracellular vesicles (st-EVs), those st-EVs stimulate dermal papilla cells to secrete norrin, which then activates follicular keratinocytes.

According to the Genetics Home Reference of the U.S. National Library of Medicine, a resource of the U.S. National Institutes of Health, “The NDP gene provides instructions for making a protein called norrin. Norrin participates in chemical signaling pathways that affect the way cells and tissues develop. Studies suggest that norrin may play a role in Wnt signaling, which is important for cell division (proliferation), attachment of cells to one another (adhesion), cell movement (migration), and many other cellular activities.

“Norrin is one of many proteins, or ligands, that can attach (bind) to other proteins called frizzled receptors. These receptors are embedded in the outer membranes of cells. Norrin binds with the receptor frizzled-4 (produced from the FZD4 gene), fitting together like a key in a lock. When a ligand binds to a frizzled receptor, it initiates a multi-step process that regulates the activity of certain genes.”

“Remarkably, [a] norrin-specific receptor, called Frizzled4, is absent from follicular keratinocytes. We showed here that dermal fibroblast EVs carry at their surface Frizzled4 to allow norrin signaling and hair growth,” Aberdam commented in a statement. “As such, our study identifies dermal fibroblast EVs as efficient activators of dermal papilla cells, and norrin as a novel player in regulating hair growth in normal and pathological conditions.”