# Live Imaging of Skin Regeneration

> **NIH NIH R01** · YALE UNIVERSITY · 2023 · $692,943

## Abstract

Summary
 Tissue homeostasis and regeneration are sustained by continuous self-renewal and differentiation of
stem cells. Failure to balance these processes is associated with diverse and common public health issues, such
as cancer and degenerative diseases. Discovering the mechanisms that regulate stem cell decisions is
fundamentally important but has been stymied by the inability to study these dynamic processes in an intact
mammal. My group overcomes this obstacle by leveraging the unique accessibility of the skin and our novel
intravital imaging approaches to track epithelial cells in real time in live animals. We have so far used this
approach to comprehensively identify all fate decisions within the epidermis, allowing us to uncover complex
relationships between stem cell behaviors. This has led to our conceptually innovative model that stem cells are
on a continuum of differentiation, coordinating their progression through the continuum based on tissue demand.
Despite these advances, how cell fate decisions are molecularly orchestrated on the tissue-level remains
unclear.
 Here, we adapt our intravital imaging techniques to visualize key molecular events – changes to
transcription, chromatin structure, and signaling pathway activation – and determine their role in population-level
coordination of cell fate decisions. We hypothesize that a global mechanism underlies the local coordination of
stem cell states, and that this mechanism is essential to ensure skin homeostasis. To test this hypothesis, we
will determine how differentiation is initiated (Aim 1). We identified a population of cells in the basal layer that co-
express stem- and differentiation-markers but do not display morphological signs of differentiation. To determine
if these cells are in a reversible transition from stemness to differentiation, we will interrogate their transcriptional
plasticity, chromatin rearrangements, and cell-extrinsic regulators. In Aim 2, we will define intercellular signaling
patterns that coordinate stem cell and differentiation behaviors. Calcium signaling acts as a signal integrator in
the late stages of epidermal differentiation and in wound-healing, and our preliminary data show that calcium
signaling is prevalent and dynamic in the basal epidermis. To define how calcium signaling intersects with the
coordination of stem cell fate decisions, we will uncover the high-order dynamics of calcium signaling in the basal
layer and determine how calcium signaling regulates the coordination of cell cycles, self-renewal, and
differentiation of basal cells. To achieve these aims, we will use an integrated approach of cutting-edge imaging
technology, transcriptomics, mouse genetics, and machine learning. This research is significant because we
expect to uncover global molecular mechanisms that coordinate stem cell self-renewal and differentiation in a
live mammal. Our findings will likely drive innovation in related fields, given that many principles of stem...

## Key facts

- **NIH application ID:** 10693376
- **Project number:** 5R01AR063663-12
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** Valentina Greco
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $692,943
- **Award type:** 5
- **Project period:** 2012-09-07 → 2027-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10693376

## Citation

> US National Institutes of Health, RePORTER application 10693376, Live Imaging of Skin Regeneration (5R01AR063663-12). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10693376. Licensed CC0.

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