# Project 2 - Macrophage regulation of fibrosis and scarring during tissue regeneration

> **NIH NIH P20** · MOUNT DESERT ISLAND BIOLOGICAL LAB · 2022 · $288,075

## Abstract

PROJECT 2 (Godwin) PROJECT SUMMARY 
 The lack of scar-free healing and regeneration in humans imposes severe limitations on functional 
recovery after major traumatic injury, surgical interventions and disease. Default wound-repair in most adult 
human tissues initiates the formation of a protein/carbohydrate fibrotic network that progressively matures into 
dysfunctional scar tissue. In organs like the heart, lung and liver, formation of scar tissue can be deadly and 
contributes to ~45% of all U.S. deaths. Development of therapies that activate regeneration and scar-free 
repair programs in humans will transform modern healthcare. 
 In contrast to humans and most other mammals, salamanders are capable of scar-free regeneration of 
almost all complex tissues including the limbs, heart, brain and spinal cord. Using the salamander as a model 
system, we recently demonstrated for the first time the critical role of the innate immune system in regulating 
scar-free regeneration. Specifically, we showed 1) that early infiltration of macrophages into damaged limb or 
heart tissue actively suppresses fibrosis and 2) that suppression of fibrosis is an essential step required for 
normal regeneration to occur. 
 The cellular and molecular mechanisms by which macrophages suppress fibrosis after injury are 
completely unknown. The overarching goal of this proposal is to begin defining these mechanisms for 
the first time using salamander limb regeneration as a model system. Development of therapies that 
suppress fibrosis by modulating macrophage function may allow scar-free repair and regeneration of damaged 
tissues in humans. 
 Our proposal will be the first to define how salamander macrophages suppress myofibroblast induction 
and scar tissue formation. We will use lineage tracing methods to identify the source of scar producing cells, 
which are the cellular targets of anti-fibrotic macrophage signaling. We will then define the macrophage 
subtypes that inhibit myofibroblast induction and fibrotic activation signals. Using RNA-sequencing, we will 
characterize gene expression patterns in macrophages that suppress myofibroblast induction. These studies 
will provide the first mechanistic insights into anti-fibrotic signaling pathways that allow macrophages to support 
scar-free healing. Finally, we will test the hypothesis that permanent scar tissue formation may be reversible 
by inhibition of lysyl oxidase, an enzyme that mediates crosslinking of the extracellular matrix, which, in turn, 
prevents scar-free healing and regeneration. 
 This proposal is both significant and innovative as it will address a critical gap in our understanding of 
how fibrosis and scarring is overcome in a highly regenerative animal model. These new insights will 
form an essential step in the development of anti-fibrosis and pro-regenerative therapies for patients. !

## Key facts

- **NIH application ID:** 10437783
- **Project number:** 5P20GM104318-10
- **Recipient organization:** MOUNT DESERT ISLAND BIOLOGICAL LAB
- **Principal Investigator:** James W Godwin
- **Activity code:** P20 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $288,075
- **Award type:** 5
- **Project period:** 2013-09-01 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10437783

## Citation

> US National Institutes of Health, RePORTER application 10437783, Project 2 - Macrophage regulation of fibrosis and scarring during tissue regeneration (5P20GM104318-10). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10437783. Licensed CC0.

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