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Updated: Jul 31, 2025
Author Spotlight: Streamlining Cell Analysis with an Innovative Protocol for Studying Spiny Mouse Models
Published on: November 15, 2024
An ERK-dependent molecular switch antagonizes fibrosis and promotes regeneration in spiny mice (Acomys)
Antonio Tomasso1,2,3,4,5, Tim Koopmans3,4, Philip Lijnzaad6
1Max Planck Institute for Molecular Biomedicine, Röntgenstrasse 20, Münster 48149, Germany.
Abstract:
Although most mammals heal injured tissues and organs with scarring, spiny mice (Acomys) naturally regenerate skin and complex musculoskeletal tissues. Now, the core signaling pathways driving mammalian tissue regeneration are poorly characterized. Here, we show that, while immediate extracellular signal-regulated kinase (ERK) activation is a shared feature of scarring (Mus) and regenerating (Acomys) injuries, ERK activity is only sustained at high levels during complex tissue regeneration. Following ERK inhibition, ear punch regeneration in Acomys shifted toward fibrotic repair. Using single-cell RNA sequencing, we identified ERK-responsive cell types. Loss- and gain-of-function experiments prompted us to uncover fibroblast growth factor and ErbB signaling as upstream ERK regulators of regeneration. The ectopic activation of ERK in scar-prone injuries induced a pro-regenerative response, including cell proliferation, extracellular matrix remodeling, and hair follicle neogenesis. Our data detail an important distinction in ERK activity between regenerating and poorly regenerating adult mammals and open avenues to redirect fibrotic repair toward regenerative healing.
Insights
Spiny mice regenerate tissues by sustaining high extracellular signal-regulated kinase (ERK) activity, unlike scarring mammals. Inhibiting ERK shifts regeneration to fibrosis, revealing key pathways for regenerative healing.
Area of Science:
- Mammalian tissue repair and regeneration
- Molecular signaling in healing processes
- Comparative biology of wound healing
Background:
- Most mammals exhibit scar-based healing, hindering full tissue and organ regeneration.
- Spiny mice (Acomys) possess a unique capacity for regenerating complex tissues, including skin and musculoskeletal structures.
- The molecular mechanisms governing mammalian regeneration remain largely uncharacterized.
Purpose of the Study:
- To investigate the role of extracellular signal-regulated kinase (ERK) signaling in mammalian tissue regeneration.
- To identify upstream regulators and downstream effectors of ERK in the context of regeneration versus scarring.
- To explore the potential of manipulating ERK activity to promote regenerative healing.
Main Methods:
- Comparative analysis of ERK activation in regenerating (Acomys) and scarring (Mus) injuries.
- Pharmacological inhibition of ERK signaling in Acomys ear punch regeneration models.
- Single-cell RNA sequencing to identify ERK-responsive cell populations.
- Loss- and gain-of-function experiments to elucidate upstream signaling pathways (FGF, ErbB).
Main Results:
- Sustained high-level ERK activity is crucial for Acomys tissue regeneration, whereas transient activation occurs in scarring.
- ERK inhibition in Acomys leads to a shift from regeneration to fibrotic repair.
- Fibroblast growth factor (FGF) and ErbB signaling pathways were identified as upstream regulators of ERK in regeneration.
- Ectopic ERK activation in scar-prone injuries promoted regenerative characteristics like cell proliferation and neogenesis.
Conclusions:
- Sustained ERK signaling is a key differentiator between regenerative and scarring healing in adult mammals.
- Targeting ERK pathways, potentially modulated by FGF and ErbB, offers a strategy to enhance regenerative capacity.
- These findings provide insights into redirecting fibrotic repair towards true tissue regeneration.
