# Investigating the role of Lef1 in fibroblast lineages to induce skin regeneration and reverse aging

> **NIH NIH R01** · WASHINGTON STATE UNIVERSITY · 2022 · $316,572

## Abstract

PROJECT SUMMARY/ABSTRACT
Understanding how to induce skin regeneration instead of scarring will have broad implications clinically and
cosmetically because; they inhibit mobility, are painful, and are a source of psychological trauma. In the United
States, treatment for burn victims alone amounts to $7.5 billion annually, the total market for scar treatment is
estimated to be around $12 billion. A lack of understanding of the role of fibroblast heterogeneity inhibits progress
in developing novel treatments for clinical conditions associated with scarring, such as, scleroderma, diabetic
ulcers, psoriasis and fibrotic keloid scarring. Consequently, understanding how to regenerate skin has the
potential to impact anyone who undergoes surgery, but also individuals with clinical conditions associated with
scarring. Adult skin wounds heal with scars, but embryonic skin can regenerate without scarring. However, not
knowing how to safely transfer the regeneration abilities of embryonic skin to adult skin remains a gap in
knowledge. Thus, the long term goal of our research is to establish methods to induce fibroblasts in adult skin to
have the same regenerative potential as their embryonic skin counterparts, without altering development and
homeostasis. The objective of this application is to induce adult fibroblasts with embryonic transcription factors
to reprogram skin to support regeneration and reverse aging. Embryonic and Neonatal skin have a transient
Papillary Fibroblasts (PFs) that are lost during skin maturation and aging. Neonatal PFs reside beneath the
epidermis, support skin regeneration, and express the canonical Wnt transcription factor, Lef1. A hallmark of
skin aging is the degradation of PFs and the loss of Lef1 expression. Our central hypothesis is that Lef1 is the
master regulator of Neonatal PF function, which induces scar-less skin regeneration and will restore PF identity
in aged skin. Guided by our exciting preliminary data we will use novel transgenic mouse models and next
generation sequencing technologies to investigate this hypothesis by the following specific aims: In aim 1 we will
test the hypothesis that Lef1 is the master regulator of Neonatal PF function by tissue specific induction in adult
skin. Here we will use wounding experiments and chamber grafting assays to test if adult scarring fibroblasts
can be transformed to be regenerative. In aim 2, we will define the downstream pathways that Lef1 regulates to
specify Neonatal PF functions. To do this we will perform ChIPSeq and Single-Cell-RNA-Seq with our
regenerative transgenic model systems. Finally, in aim 3 we will determine if Lef1 can safely restore Neonatal
PF identity and function in aged skin. We will analyze “old” transgenic mice with reprogrammed skin and test
their ability to regenerate skin and inhibit “aging”. This proposal is innovative because of our novel approach of
manipulating embryonic transcription factors in fibroblasts in vivo. The proposed research i...

## Key facts

- **NIH application ID:** 10402885
- **Project number:** 5R01AR078743-02
- **Recipient organization:** WASHINGTON STATE UNIVERSITY
- **Principal Investigator:** Ryan Driskell
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $316,572
- **Award type:** 5
- **Project period:** 2021-05-07 → 2026-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10402885

## Citation

> US National Institutes of Health, RePORTER application 10402885, Investigating the role of Lef1 in fibroblast lineages to induce skin regeneration and reverse aging (5R01AR078743-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10402885. Licensed CC0.

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