# Investigating macrophage assisted reprogramming of lizard fibroblasts during appendage regeneration

> **NIH NIH F31** · UNIVERSITY OF SOUTHERN CALIFORNIA · 2024 · $45,574

## Abstract

Osteoarthritis (OA) is the most common degenerative joint disease, affecting more than 27 million adults in the
United States alone. OA can be triggered by injury as well as by aging and natural wear and tear of cartilage
tissue in joints, causing degradation and damaging tissue inflammation. Currently, rehabilitation strategies for
human cartilage injuries cause complications from disorganized scarring and lack of replacement tissue growth.
A branch of regenerative medicine looks to non-mammalian species with hyper-regenerative abilities for clues
to improve human wound healing. However, this approach has struggled to (1) select appropriate model species
for meaningful translation to humans and (2) identify specific, actionable molecular targets for manipulating
regenerative capabilities. Lizards are the only adult amniotes and closest relatives of humans able to suppress
fibrosis and regenerate hyaline cartilage. This extraordinary process involves the formation of specialized
regenerative structures known as blastemas, collections of reprogrammed fibroblasts that differentiate into
replacement tissues. Robust macrophage activity at cartilage injury sites is observed and correlates with the
proliferation of resting COL3+ fibroblasts. By day 14, these COL3+ fibroblasts undergo sequential gene
activation, resulting in a mass of mesenchyme-derived multipotent cells called a blastema. We have shown that
blastema cells are Hedgehog responsive, SULF1+, multipotent cells capable of differentiating into ACAN+
hyaline cartilage. Inhibition of inflammation using macrophage depletion agents prevents blastema formation
from occurring, resulting in a fibrotic scar. The dichotomy of inflammation stimulating regeneration in the lizard
compared to inflammation causing fibrotic scaring in the case of human OA is striking, especially considering
that similar inflammatory mechanistic machinery, such as GP130, is shown to be activated in both lizards and
humans. GP130 is an IL-6 family cytokine receptor reported to stimulate either pro-fibrotic or pro-regenerative
genes-based epigenetic remodeling of inflamed tissue cells. We hypothesize that macrophage-induced
GP130/STAT3 signaling reprograms wound fibroblasts to a blastema cell state by opening chromatin
accessibilities of pro-regenerative, chondrogenic gene enhancers and closing pro-fibrotic gene regions in lizards.
Aim 1 will Investigate the role of STAT3 signaling in transitioning resting fibroblasts to chondrogenic blastema
cells. Aim 2 will determine the role of macrophages in regulating STAT3 signaling in lizard fibroblasts during
blastema formation and chondrogenesis. An integrated approach incorporating GP130/STAT3 modulating drugs
and next-generation epigenetic sequencing will allow us to identify critical pro-regenerative genes and enhancers
to serve as potential targets for hyaline cartilage regeneration in humans to treat OA. Recreating the earliest
stages of lizard blastema formation in human patien...

## Key facts

- **NIH application ID:** 10998300
- **Project number:** 1F31GM151835-01A1
- **Recipient organization:** UNIVERSITY OF SOUTHERN CALIFORNIA
- **Principal Investigator:** Darian Gamble
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $45,574
- **Award type:** 1
- **Project period:** 2024-08-01 → 2026-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10998300

## Citation

> US National Institutes of Health, RePORTER application 10998300, Investigating macrophage assisted reprogramming of lizard fibroblasts during appendage regeneration (1F31GM151835-01A1). Retrieved via AI Analytics 2026-06-16 from https://api.ai-analytics.org/grant/nih/10998300. Licensed CC0.

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