Mount Sinai Researchers Identify Details of Muscle’s Role in Regulating Hair Growth Cycle
Discovery could improve development of future hair loss treatments
Paper Title: Progenitor-derived endothelin controls dermal sheath contraction for hair follicle regression
Journal: Nature Cell Biology (January 30, 2023)
Authors: Michael Rendl, MD, Professor of Cell, Developmental and Regenerative Biology, and Dermatology, and Associate Director, Black Family Stem Cell Institute, at the Icahn School of Medicine at Mount Sinai; and other coauthors.
Bottom Line: Hair growth occurs in a cycle starting with growth of the hair from a follicle, followed by a regression phase in which the follicle recedes and an inactive resting phase, then the regrowth of the follicle from stem cells. The newly formed follicle produces new hair after which the old hair is shed. Drastic hair follicle changes during the regression phase are coordinated by contraction of the dermal sheath smooth muscle. But how the contraction of the sheath muscle is regulated is largely unknown. This new study identifies space- and time-controlled endothelin signaling, a well-known pathway that otherwise regulates the narrowing of blood vessels to help control blood pressure, as the key activating mechanism of sheath contraction. Medications that block both endothelin receptors ETA and ETB, or removal of gene expression with genetically modified DNA in mice, impede dermal sheath contraction and halt follicle regression. Cells known as progenitors, which originated from stem cells and are located at the bottleneck structures of regressing hair follicles in the outer layer of the skin surface, produce endothelin-1, a small protein that constricts blood vessels and is required for follicle regression. Endothelin-1 signaling in dermal sheath cells and downstream contraction are regulated by calcium levels in the cytoplasm, a fluid that protects and holds the components of cells, through channels in the cell membrane.
How: The researchers first obtained pure dermal sheath cells during the transition from tissue growth to regression using fluorescence-activated cell sorting of cells from the back skins of mice and performed transcriptomic analyses discovering endothelin receptor expression.
Results: Using their analysis, the researchers identified endothelin signaling as a potential dermal sheath contraction-activating pathway. Functional and genetic manipulations of the endothelin receptors established the need for endothelin signaling in dermal sheath contraction and hair follicle regression. Furthermore, spatiotemporal examination of protein expression for endothelin-1 uncovered signaling from nearby progenitors. Examining the molecular mechanisms of endothelin signaling in cultured dermal sheath cells confirmed that this small protein triggers contraction in the dermal sheath through cytoplasmic calcium channels in the plasma membrane and skeletal muscle cells.
Why the Research Is Interesting: A potent muscle-contraction signaling pathway activated by progenitor cells controls the contraction of the cells surrounding hair follicles, which is essential for regression during the normal hair growth cycle. These findings reveal an interaction between mesenchymal and epithelial cells in which progenitors, which ultimately undergo cell death, control the contraction of the surrounding sheath smooth muscle to manage tissue regression and reorganization for the next stem cell activation and regeneration cycle. This discovery has implications for development of treatment for hair loss.
Said Dr. Rendl of the research: “Our study highlights that progenitors orchestrate remodeling of their microenvironment during tissue regression, in addition to their well-known role as the main architects of the stem cell niche during homeostasis and regeneration. It will be interesting to determine whether endothelin-induced contraction can also regulate other hair cycle phases. From a translational point of view, it may be beneficial to explore contraction-blocking strategies to ameliorate hair loss conditions. Further studies will be important to determine the upstream transcriptional regulation of endothelin expression in progenitors in the bottleneck region of the follicle.”
Researchers from the University of Utah Health in Salt Lake City, Utah, and the University of Tsukuba in Tsukuba, Japan, contributed to this study.
View the full paper here. To schedule an interview with Dr. Rendl, contact the Mount Sinai Press Office at stacy.anderson@mountsinai.org or 347-346-3390.
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