# Multiscale Models of Wound Cell Plasticity for Regeneration

> **NIH NIH U01** · UNIVERSITY OF CALIFORNIA-IRVINE · 2021 · $10,106

## Abstract

In regenerative medicine, it is critically important to understand the complex mechanisms that rewrite and
stably maintain cellular memory in order to reprogram cells to the new, desired destination fates. Wound
healing, involving critical biological processes at multiple spatial and temporal scales, provides an ideal system
for studying regenerative mechanisms. In skin, several distinct pools of epithelial stem cells, such as those in
the interfollicular epidermis and different parts of the hair follicle, become activated and recruited to repair the
wound. Importantly, large skin wounds can regenerate the normal array of tissue constituents, specifically new
hairs, while small wounds never can. We hypothesize that regeneration is an emerging property arising from
the optimal interplay between many biological events at multiple temporal and spatial scales including, but not
limited to, transcriptional reprogramming of migrating epidermal, dermal and immune cells, as well as signaling
crosstalk between these cells and their surrounding microenvironment. Here, we propose a novel multiscale
framework integrating multiple physiological systems (e.g. epidermal, dermal, and immune cells and hair
follicles) to identify critical conditions for shifting injury repair toward regeneration and away from scarring. The
proposed methodology addresses cutting-edge multiscale challenges in analyzing single-cell molecular data
and their connections with spatial dynamics in tissues. We will carry out three aims. In Aim 1, we will identify
regeneration-specific gene profile changes in epidermal, dermal, and immune cell in healing wounds; in Aim 2,
we will develop an integrative multiscale model to predict the relative roles and emergent dynamics of multiple
interacting cell types during wound healing; and in Aim 3, we will test model predictions using in-vivo murine
functional assays and ex vivo human co-culture; in combination with multiscale simulations and statistical
inference, we will thus be able to dissect the regenerative roles and spatial dynamics of candidate regulators.
The knowledge gained in this proposed work will help to develop future protocols for augmenting the
regeneration mechanisms in clinical settings to achieve robust human skin regeneration after any injury (small
or large) and with high efficiency (i.e. always achieve high density of regenerating hairs). The overall insights
learned will not only shed new light into skin research, but also establish a founding paradigm for other
epithelial systems. The novel computational tools for single-cell RNA-seq-driven cell lineage tracking, the
robust multiscale models for spatial dynamics of multiple cell lineages, and the overall integrative multiscale
framework of tissue regeneration will have broad applications, including for embryonic development, solid
tumors, and many other epithelial and even non-epithelial tissues. Given the importance of stem/progenitor
cells in regeneration and tumorigenesi...

## Key facts

- **NIH application ID:** 10289695
- **Project number:** 3U01AR073159-03S1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA-IRVINE
- **Principal Investigator:** Xing Dai
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $10,106
- **Award type:** 3
- **Project period:** 2021-01-01 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10289695

## Citation

> US National Institutes of Health, RePORTER application 10289695, Multiscale Models of Wound Cell Plasticity for Regeneration (3U01AR073159-03S1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10289695. Licensed CC0.

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