# Specification, Molecular Control and Niche Functions of the Hair Follicle Mesenchyme

> **NIH NIH R01** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2022 · $608,708

## Abstract

Project Summary
During the hair cycle, growing hair follicles (HF) regress in a phase marked by progenitor death and follicle
remodeling (catagen), before a rest period (telogen) and new hair growth (anagen). Signals from the dermal
papilla (DP) – a key signaling center – regulate progenitor proliferation and differentiation in the bulb of growing
HFs, and induce bulge/germ stem cells (SC) to regenerate fully growing HFs. During catagen regression, the
DP needs to relocate from the base of growing HFs to the SC reservoir in the upper HF, traversing the skin
several hundred micrometers. How this is accomplished has been unknown for decades. In the first funding
period, we have uncovered that the follicle-lining dermal sheath (DS) is a smooth muscle that contracts to
physically relocate the DP to reach its essential SC-adjacent position. The dynamic molecular changes that occur
in adjacent progenitors and the DS and whether epithelial-mesenchymal crosstalk between them regulates
contraction is unknown. Exploring our DS and several other gene signatures suggested an intriguing role of
endothelin signaling, a well-known vasoconstriction regulatory pathway, in controlling DS contraction. With
several established and newly developed functional assays and novel genetic DS targeting, we have now
established the conditions for exploring the dynamic expression of endothelin ligand, receptor and other pathway
members in progenitors, DS and DP during both growth and regression; for investigating the functional role(s)
of progenitor-derived endothelin in signaling and activating contraction; and for dissecting the downstream
pathway mechanism(s). Overall, we will rigorously test the hypothesis that follicle progenitors and the DS engage
in epithelial-mesenchymal crosstalk crucial for regulating DS contraction and hair cycle regression. We will
precisely map expression localization and timing of key endothelin signaling pathway members through detailed
in situ hybridization and immunofluorescence analyses. We will further purify DS and progenitors with novel
multicolor isolation methods from growing and regressing follicles and analyze their transcriptomes to define
potential signaling crosstalk in general and all components of the endothelin pathway system in particular. We
will pharmacologically activate and block endothelin signaling activation in isolated DS cells and microdissected
follicles, and determine functional DS contraction in our recently established in vitro and ex vivo live imaging
assays. We will then explore the consequences of contraction inhibition in vivo and directly visualize contraction
inhibition with intravital imaging. We will perform timed genetic receptor and ligand ablations and assess the
impact on follicle regression. Finally, we will define the spatial and temporal calcium signaling dynamics
downstream of endothelin pathway activation using calcium reporter mice and activators and inhibitors of Ca2+
channels as well as of the P...

## Key facts

- **NIH application ID:** 10449198
- **Project number:** 5R01AR071047-07
- **Recipient organization:** ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
- **Principal Investigator:** Michael Rendl
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $608,708
- **Award type:** 5
- **Project period:** 2016-09-15 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10449198

## Citation

> US National Institutes of Health, RePORTER application 10449198, Specification, Molecular Control and Niche Functions of the Hair Follicle Mesenchyme (5R01AR071047-07). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10449198. Licensed CC0.

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