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An ERK-dependent molecular switch antagonizes fibrosis and promotes regeneration in spiny mice (Acomys)

ABSTRACT: Although most mammals heal injured tissues and organs with scarring, spiny mice (Acomys) naturally regenerate skin and complex musculoskeletal tissues. Currently, the core signaling pathways driving mammalian tissue regeneration are poorly characterized. Here, we show that, while immediate 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 towards fibrotic repair. Using scRNA-seq, we identified ERK-responsive cell types. Loss- and gain-of-function experiments prompted us to uncover FGF and ErbB signaling as upstream ERK regulators of regeneration. Strikingly, 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 towards regenerative healing.

ORGANISM(S): Acomys cahirinus

PROVIDER: GSE224879 | GEO | 2023/04/28

REPOSITORIES: GEO

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An ERK-dependent molecular switch antagonizes fibrosis and promotes regeneration in spiny mice (Acomys)

Project description:Although most mammals heal injured tissues and organs with scarring, spiny mice (Acomys) naturally regenerate skin and complex musculoskeletal tissues. Currently, the core signaling pathways driving mammalian tissue regeneration are poorly characterized. Here, we show that, while immediate ERK activation is a shared feature of scarring (Mus) and regenerating (Acomys) injuries, ERK activity is only sustained during complex tissue regeneration. Following ERK inhibition, regeneration in Acomys shifted towards a fibrotic repair. Using scRNA-seq, we uncovered that MAPK/ERK signaling acts in a cell type specific manner to direct regenerative healing. Loss- and gain-of-function experiments prompted us to identify FGF and ErbB signaling as upstream ERK regulators of regeneration. By ectopically activating ERK in Mus injuries, a pro- regenerative response was induced, including cell proliferation, extracellular matrix remodeling and hair follicle neogenesis. Our data provide new insights into why some mammals regenerate better than others and open avenues to redirect fibrotic repair towards regenerative healing.

2023-04-28 | GSE224433 | GEO

Comparative Proteomic Analysis in Acomys cahirinus

Project description:Comparative Proteomic Analysis in Scar-Free Skin Regeneration in Acomys cahirinus and Scarring Mus musculus

2019-11-19 | MSV000084597 | MassIVE

Proteomic Analysis in Scar-Free Skin Regeneration in Acomys cahirinus

Project description:Comparative Proteomic Analysis in Scar-Free Skin Regeneration in Acomys cahirinus and Scarring Mus musculus

2019-11-24 | MSV000084615 | MassIVE

Comparing regeneration and fibrosis using Acomys and Mus

Project description:This project is designed to find differentially expressed genes between regeneration and fibrosis in Acomys (regenerator) and Mus (non-regenerator)

2016-03-17 | GSE71761 | GEO

Comparison of gene expression in cardiac macrophages from P1 or P14 mice 3 days following MI

Project description:Myocardial infarction (MI) leads to cardiomyocyte death, which triggers an immune response that clears debris and restores tissue integrity. In the adult heart, the immune system facilitates scar formation, which repairs the damaged myocardium but compromises cardiac function. In neonatal mice, the heart can regenerate fully without scarring following MI; however, this regenerative capacity is lost by P7. The signals that govern neonatal heart regeneration are unknown. By comparing the immune response to MI in mice at P1 and P14, we identified differences in the magnitude and kinetics of monocyte and macrophage responses to injury. Using a cell-depletion model, we determined that heart regeneration and neoangiogenesis following MI depends on neonatal macrophages. Neonates depleted of macrophages were unable to regenerate myocardia and formed fibrotic scars, resulting in reduced cardiac function and angiogenesis. Immunophenotyping and gene expression profiling of cardiac macrophages from regenerating and nonregenerating hearts indicated that regenerative macrophages have a unique polarization phenotype and secrete numerous soluble factors that may facilitate the formation of new myocardium. Our findings suggest that macrophages provide necessary signals to drive angiogenesis and regeneration of the neonatal mouse heart. Modulating inflammation may provide a key therapeutic strategy to support heart regeneration. Total RNA was isolated from CD11b+Ly6G- cells sorted from hearts 3 days following ligation of LAD. 6 samples total: Triplicates of cells from P1 mice and from P14 mice

2014-01-31 | E-GEOD-54530 | biostudies-arrayexpress

Multi-omic analysis reveals divergent molecular events in scarring and regenerative wound healing

Project description:Regeneration is the “holy grail” of tissue repair, but skin injury typically yields fibrotic, non-functional scars. Developing pro-regenerative therapies requires rigorous understanding of the molecular progression from injury to fibrosis or regeneration. Here, we report the divergent molecular events driving skin wound cells toward either scarring or regenerative fates. We profile scarring versus YAP inhibition-induced wound regeneration at the transcriptional (single-cell RNA-sequencing), protein (timsTOF proteomics), and tissue (extracellular matrix ultrastructural analysis) levels. Using cell surface barcoding, we integrate these data to reveal fibrotic and regenerative “molecular trajectories” of healing. We show that disrupting YAP mechanical signaling yields regenerative repair orchestrated by fibroblasts with activated Trps1 and Wnt signaling. Finally, by performing in vivo gene knockdown and overexpression in wounds, we identify Trps1 as a key regulatory gene that is necessary and partially sufficient for wound regeneration. Our findings serve as a multimodal map of wound regeneration and could have therapeutic implications for pathologic fibroses.

2022-01-24 | GSE186527 | GEO

Acomys

Project description:Acomys Raw sequence reads

| PRJNA323834 | ENA

A Comparative Analysis of Gene Expression Profiles During Skin Regeneration in Mus and Acomys

Project description:Acomys exhibits a blunted immune response to wounding, and shares characteristics with fetal wound healing We used mouse microarrays to compare gene expression profiles during wound healing between the African spiny mouse (Acomys) and the house mouse (Mus)

2015-10-28 | E-GEOD-74387 | biostudies-arrayexpress

Acomys cahirinus

Project description:Acomys cahirinus overview

| PRJNA188251 | ENA

Exosomal proteins identification from neonatal mouse plasma

Project description:Paracrine effects mediated by exosomes contribute to the major regenerative functions of cell therapies after myocardial injuries. Early neonatal mammals retain a transient regeneration capacity after heart injury, which reminds us to explore the cardioprotective and regenerative potency of plasma exosomes from neonatal mouse (npEXO). Therefore, we isolated plasma exosomes from neonatal mice and performed proteomic analysis.

2022-12-13 | PXD038805 | iProX

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