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)
Project description:Purpose: The goal of this study was to characterize the kidney transcriptome of Mus musculus and Acomys cahirinus after unilateral ureteral obstruction (UUO) kidney injury. Methods: Kidney mRNA-seq profiles of 10 week old mouse and spiny mouse were generated at 2 day and 5 days after unilateral ureteral obstruction injury in triplicate, using Illumina NovaSeq 6000. The sequence reads that passed quality filters were analyzed at the transcript isoform level with Salmon, edgeR and a limma-voom pipeline in R. Results: For both Mus musculus and Acomys cahirinus kidneys, we mapped about 50 million sequence reads per sample to the mouse transcriptome and identified 20580 transcripts in kidneys of Mus musculus and 54075 transcripts in the kidneys of Acomys cahirinus. Using 1.5 fold change and FDR < 0.05, number of transcripts that are significantly different between Mus musculus samples: 3915 between normal and day 2 after UUO, 5365 between normal and day 5 after UUO. For Acomys cahirinus: 1765 between normal and day 2 after UUO, 2499 between normal and day 5 after UUO. Conclusions: Our study demonstrate there were many conserved responses to kidney injury between M. musculus and A. cahirinus despite the divergent outcomes for kidney fibrosis.
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 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.
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.
Project description:Tissue regeneration is a process that recapitulates the molecular and mechanical aspects of development and evolution. We use the wound-induced hair neogenesis (WIHN) model to investigate the mechanical and molecular responses of the laboratory (Mus) and African spiny (Acomys) mice. Laboratory and spiny mice showed an opposite trend of spatiotemporal morphogenetic field for WIHN during wound healing, and wound stiffness gradient across the whole wound bed predicated pattern of hair formation. Using bulk and single-cell RNA-seq analysis and K14-Cre-Twist1 transgenic mice, we identified the central role of the Twist1 pathway as the mediator of epidermal-dermal interaction and the emergence of periodic hair primordia. Lastly, we generated a Turing model with an underlying measure of stiffness to support a two-scale tissue mechanic model to explain the setup of a morphogenetic field from a wound bed (mm scale) or periodically arranged hair primordia from a morphogenetic field (μm scale). Delineating the common and distinct chemo-mechanical events during regenerative wound healing between laboratory and African spiny mice reveal its evo-devo advantages, which provide new perspectives for regenerative medicine.
Project description:Tissue regeneration is a process that recapitulates the molecular and mechanical aspects of development and evolution. We use the wound-induced hair neogenesis (WIHN) model to investigate the mechanical and molecular responses of the laboratory (Mus) and African spiny (Acomys) mice. Laboratory and spiny mice showed an opposite trend of spatiotemporal morphogenetic field for WIHN during wound healing, and wound stiffness gradient across the whole wound bed predicated pattern of hair formation. Using bulk and single-cell RNA-seq analysis and K14-Cre-Twist1 transgenic mice, we identified the central role of the Twist1 pathway as the mediator of epidermal-dermal interaction and the emergence of periodic hair primordia. Lastly, we generated a Turing model with an underlying measure of stiffness to support a two-scale tissue mechanic model to explain the setup of a morphogenetic field from a wound bed (mm scale) or periodically arranged hair primordia from a morphogenetic field (μm scale). Delineating the common and distinct chemo-mechanical events during regenerative wound healing between laboratory and African spiny mice reveal its evo-devo advantages, which provide new perspectives for regenerative medicine.