Cas9-Mediated Knockout of Ndrg2 Enhances the Regenerative Potential of Dendritic Cells for Wound Healing
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PROVIDER: PRJNA980198 | ENA |
REPOSITORIES: ENA
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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
Project description:Chronic wounds impose a significant healthcare burden to a broad patient population. Cell-based therapies, while having shown benefits for the treatment of chronic wounds, have not yet achieved widespread adoption into clinical practice. We developed a CRISPR/Cas9 approach to precisely edit murine dendritic cells to enhance their therapeutic potential for healing chronic wounds. Using single-cell RNA sequencing of tolerogenic dendritic cells, we identified N-myc downregulated gene 2 (Ndrg2), which marks a specific population of dendritic cell progenitors, as a promising target for CRISPR knockout. Ndrg2-knockout alters the transcriptomic profile of dendritic cells and preserves an immature cell state with a strong pro-angiogenic and regenerative capacity. We then incorporated our CRISPR-based cell engineering within a therapeutic hydrogel for in vivo cell delivery and developed an effective translational approach for dendritic cell-based immunotherapy that accelerated healing of full-thickness wounds in both non-diabetic and diabetic mouse models. These findings could open the door to future clinical trials using safe gene editing in dendritic cells for treating various types of chronic wounds.
| S-EPMC10406832 | biostudies-literature
Project description:Skin wound healing due to full thickness wounds typically results in fibrosis and scarring, where parenchyma tissue is replaced with connective tissue. A major advance in wound healing research would be to instead promote tissue regeneration. Helminth parasites express excretory/secretory (ES) molecules, which can modulate mammalian host responses. One recently discovered ES protein, TGF-β mimic (TGM), binds the TGF- receptor, though likely has other activities. Here we demonstrate that topical administration of TGM under a Tegaderm bandage enhanced wound healing and tissue regeneration in an in vivo wound biopsy model. Increased restoration of normal tissue structure in the wound beds of TGM-treated mice was observed during mid- to late-stage wound healing. Both accelerated re-epithelialization and hair follicle regeneration were observed. Further analysis showed differential expansion of myeloid populations at different wound healing stages, suggesting recruitment and reprogramming of specific macrophage subsets. This study indicates a role for TGM as a potential therapeutic option for enhanced wound healing.
2024-08-19 | GSE272815 | GEO
Project description:Impaired skin wound healing is a significant global health issue, especially among the elderly. Wound healing is a well-orchestrated process involving the sequential phases of inflammation, proliferation, and tissue remodeling. Although wound healing is a highly dynamic and energy-requiring process, the role of metabolism remains largely unexplored. By combining transcriptomics and metabolomics of human skin biopsy samples, we mapped the core bioenergetic and metabolic changes in normal acute as well as chronic wounds in elderly subjects. We found upregulation of glycolysis, the tricarboxylic acid cycle, glutaminolysis, and β-oxidation in the later stages of acute wound healing and in chronic wounds. To ascertain the role of these metabolic pathways on wound healing, we targeted each pathway in a wound healing assay as well as in a human skin explant model using metabolic inhibitors and stimulants. Enhancement or inhibition of glycolysis and, to a lesser extent, glutaminolysis had a far greater impact on wound healing than similar manipulations of oxidative phosphorylation and fatty acid β-oxidation. These findings increase the understanding of wound metabolism and identify glycolysis and glutaminolysis as potential targets for therapeutic intervention.
2024-07-02 | MTBLS3315 | MetaboLights
Project description:Adult mammalian skin wound healing is typically accompanied by fibrotic scar that impairs normal skin function and regeneration of skin appendages. Interestingly, however, in adult mice, large severe skin injuries exhibit de novo formation of HFs following severe skin injuries (a phenomenon termed wound-induced HF neogenesis, WIHN). Understanding the competent cell types and molecular mechanisms that enable regenerative wound healing will be critical for developing treatments that restore skin function after injury. We described the existence of an adult bipotent hair follicle dermal stem cell (hfDSC) that functions to regenerate the connective tissue sheath and to populate the DP with new cells (Rahmani et al., 2014). Based on this, we hypothesized that the mesenchymal cells comprised within the neogenic HFs might originate from hfDSCs. To test this, we employed αSMACreERT2:ROSAYFP and Hic1CreERT2:TDTmt mice to examine the contribution of hfDSCs or hfDSCs and reticular/hypodermal progenitors, respectively, to the formation of neodermis and regeneration of de novo HFs. Mice received full-thickness excision wounds (>1 cm2) and then harvested at 18-140 days post-wounding (dpw). αSMA+ve and Hic1-lineage cells were activated upon wounding, migrated into the wound, and contributed to both DP and DS in almost all de novo-formed HFs. Surprisingly, hfDSCs contributed only a minority of cells (20%) to nascent DP cells, whereas Hic1-lineage cells generated >90% of the neogenic DP cells. In both cases, cells integrating into neogenic HF mesenchyme appeared to restore the hfDSC pool, since they repopulated the neogenic mesenchyme over successive regenerative hair cycles. Finally, using an ex vivo HF formation assay, we found that prospectively isolated extrafollicular Hic-lineage cells could participate in HF formation when exposed to a permissive environment. Our data reveal that despite their origin in the reticular/hypodermis, Hic1-lineage dermal progenitors are able to adopt a regenerative response during wound healing if provided with a permissive local environment.
2020-08-04 | GSE108677 | GEO
Project description:Hypoxia is one of the factors that govern reparative vs regenerative skin wound healing. Data-independent acquisition (DIA) experiment was carried out to study the effect of hypoxia and Foxn1 on mice dermal fibroblast proteomics signature and skin wound healing of Foxn1-deficient (Foxn1-/-) mice.
2024-06-20 | PXD041939 | Pride
Project description:Uninjured skin of adult C57BL/6J mice and mouse fetuses at 18 day of embryonic development (E18), as the models of reparative healing, and Nude and E14, as the models of regenerative healing, were characterized for their gene expression profiles by next-generation high-throughput DNA sequencing. The comparisons of gene expression profiles indicated that there were more similarities within each model of healing (Nude was more similar to E14 and B6 was more similar to E18). The analysis revealed that Nude and E14 showed in common the up-regulation of genes associated with tissue remodeling, cytoskeletal rearrangements, wound healing and immune response and the down-regulation of genes coupled to differentiation. Gene expression profiles of regenerative adult Nude mice display features of an attenuated skin development resembling that of E14 mice, thus the Nude mouse may be considered as a unique example of neoteny among mammals. The similar expression profiles of genes in the skin of both Nude and E14 mice are direct or indirect consequences of FOXN1 deficiency. FOXN1 appears to regulate the balance between cell proliferation and differentiation and its lack creates a pro-regenerative environment.
2016-12-30 | GSE71619 | GEO
Project description:The aim of this study was to assess the effect induced by high fish density on cutaneous wound healing in post-smolt Atlantic salmon. Our findings suggest that high fish density enhances inflammation and represses cell proliferation, tissue secretion and collagen synthesis in the healing wounds. These processes are further manifested in the different layers of the skin, such as delayed re-epithelialization, altered mucus response, reduced scale mineralization, enhanced wound pigmentation and delayed organization of dense connective tissue. Temporarily changes in wound healing mechanisms result in permanent differences in wound contraction. In conclusion, our results show that high fish density dispose the fish for an enhanced immune response and delayed tissue repair, which ultimately results in delayed wound healing.
2018-11-06 | GSE122142 | GEO
Project description:Multi-omic analysis reveals divergent molecular events in scarring and regenerative wound healing
| PRJNA774283 | ENA