# Rapid functional genetics to study stem cell-niche interactions in the skin

> **NIH NIH R01** · HARVARD UNIVERSITY · 2022 · $520,520

## Abstract

Project Summary
Skin stem cells are heavily influenced by signals from their niches including different fibroblasts populations.
While our ability to isolate and molecularly profile diverse cell types has improved drastically in the past decade,
a major roadblock in identifying key genes driving stem cell-niche interactions is the lengthy process of
generating the genetic models needed (e.g., cell-type specific Cre or CreER, and overexpression or knockout
mouse lines) to test gene functions in a cell-type specific manner in a physiologically relevant context. As such,
while many different cell types have been identified and molecularly profiled, the critical genes that drive many
developmental and regeneration processes remain incompletely understood. This substantial knowledge gap
presents a significant impediment to developing therapies for skin diseases.
To address this gap and to showcase how rapid functional genetics can enable new discoveries in stem cell-
niche interactions, we will first build adeno-associated viral (AAV) toolkits to expand the field’s capacity for rapid
functional genetics in multiple dermal cell types in mice. This aim expands on our current success in using AAVs
to transduce dermal cells, with the goal of building tools that allows all skin researchers to modify gene
expression rapidly in dermal populations such as the dermal fibroblasts and DP. We have recently developed
and conducted SHARE-seq on the skin, a high-throughput single cell sequencing method that simultaneously
measures chromatin accessibility (single cell ATACseq) and gene expression (single cell RNAseq) within the
same cell. SHARE-seq data allow us to computationally infer key regulatory elements (enhancers, promoters)
of signature genes for distinct cell types, which further enables the construction of cell-type specific AAV tools.
We know the proposed strategy is feasible, because we have used it to build tools that can manipulate gene
expression in the arrector pili muscles (APMs), a cell type that currently lacks specific Cre/CreER constructs.
APMs are an emerging niche cell type for hair follicle stem cells (HFSCs). However, the molecular mechanisms
by which APMs regulates HFSC behavior remain poorly understood. In Aim2, we will use our AAV tools to
discover APM-derived secreted factors that regulate HFSC activation and maintenance. Collectively, these
results will provide the skin community with much-needed tools to accelerate research in diverse topics, and
may be relevant for understanding and potentially treating a wide range of alopecia conditions. Since AAVs are
non-toxic and non-immunogenic, and since many key tissue-specific regulatory elements retain their specificity
across species, there is an exciting potential to combine our biological findings with our technical advancements
to develop novel gene therapy strategies to treat these skin diseases in the near future.

## Key facts

- **NIH application ID:** 10341428
- **Project number:** 1R01AR080110-01
- **Recipient organization:** HARVARD UNIVERSITY
- **Principal Investigator:** Ya-Chieh Hsu
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $520,520
- **Award type:** 1
- **Project period:** 2022-02-24 → 2026-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10341428

## Citation

> US National Institutes of Health, RePORTER application 10341428, Rapid functional genetics to study stem cell-niche interactions in the skin (1R01AR080110-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10341428. Licensed CC0.

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