# Cellular and Molecular Mechanisms Underlying Merkel Cell Loss and Regeneration

> **NIH NIH R01** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2024 · $605,076

## Abstract

Summary
The mechanosensory Merkel cells (MCs) are crucial for encoding the sense of light touch. Recent studies have
shown that MCs also significantly regulate alloknesis, the itch sensation caused by light mechanical stimulation.
Notably, alloknesis is commonly observed in the elderly, with research indicating a decrease in MC numbers in
aged human and mouse skin. Among many skin abnormalities occurring with aging, dry skin condition appears
to be involved in alloknesis. In experiments using a mouse model of experimental dry skin induced by acetone-
ether-water (AEW) treatment, a decline in MC numbers and an increase in alloknesis were observed.
Interestingly, upon discontinuing the AEW treatment, MC numbers returned to normal, and the mechanical itch
was gradually alleviated. This suggests that uncovering the cellular and molecular mechanisms controlling MC
decrease or MC regeneration could pave the way to designing therapies to prevent alloknesis in aging and dry
skin. In Aim 1, we will focus on understanding the mechanisms behind the regeneration of MCs. Pilot studies
showed that MC recovery is not due to MC proliferation; however, the exact source of MC regeneration remains
unknown. We demonstrated that the Tenascin C (TNC)-expressing epidermal keratinocytes are MC progenitors.
Here, we will use lineage tracing and single-cell RNA sequencing to investigate if TNC-positive cells are
responsible for MC regeneration upon AEW treatment and to identify cellular and molecular processes controlling
MC regeneration. We will then perform genetic studies to examine the functional significance of identified
processes on MC regeneration. Finally, we will analyze molecular changes in MC progenitors and the MC
differentiation program in young vs old mice and uncover the functional significance of the identified changes on
the age-related decline of MCs. In Aim 2, we will investigate the interaction between MRGPRA3/TRPV1+ itch-
initiating C fibers and MCs, as our studies showed that the ablation of MRGPRA3/TRPV1+ neurons prevents MC
reduction upon AEW treatment. Here, we will perform chemogenetic manipulations of the activity of
MRGPRA3+/TRPV1+ sensory neurons to reveal the causal relationship between sensory neuron activities and
MC numbers. We will further identify molecules secreted by MRGPRA3/TRPV1+ neurons post-AEW treatment
and receptors of these molecules in MCs or MC progenitors, shedding light on the cellular and molecular
dynamics controlling MC numbers. We will test the functional significance of the identified ligand-receptor pairs
for controlling MC numbers and inducing alloknesis by performing functional genetic studies in the settings of
aging and dry skin. Overall, these studies aim to offer new insights into preventing age-related MC decline and
associated alloknesis, potentially leading to novel therapeutic interventions.

## Key facts

- **NIH application ID:** 10999568
- **Project number:** 1R01AG089916-01
- **Recipient organization:** ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
- **Principal Investigator:** Elena Ezhkova
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $605,076
- **Award type:** 1
- **Project period:** 2024-07-15 → 2029-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10999568

## Citation

> US National Institutes of Health, RePORTER application 10999568, Cellular and Molecular Mechanisms Underlying Merkel Cell Loss and Regeneration (1R01AG089916-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10999568. Licensed CC0.

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