Peripheral glia constitute a pro-reparative niche triggering skin wound healing
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE308799 | GEO | 2026/01/09
REPOSITORIES: GEO
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Pertinently, using the X. laevis model, previous work from our lab showed that CSF1- and IL34- macrophages are functionally distinct, formulating our hypothesis that these subsets play distinct roles during different phases of cutaneous wound repair. We therefore characterized full-thickness (epidermis and dermis) skin wounds in juvenile X. laevis during regeneration, analyzing transcript levels reflecting: M( infiltration (csf1r) and phenotype abundance (csf1 and il34), fibroblast activation (αSMA/acta2), and wound bed collagen composition (Picrosirius red staining). To assess the functional roles of macrophage phenotypes, we enriched wounds with recombinant X. laevis CSF1, IL34, or a vector control 3 days post-wounding (dpw) and analyzed wound responses at 7 and 14 dpw. Normal scarless regeneration in these juveniles demonstrated that macrophages transiently accumulated in the wound bed, peaking at 7–14 dpw. This coincided with elevated csf1 expression, which later declined as il34 levels rose. Fibroblast activation into myofibroblasts as well as collagen deposition followed this cytokine shift and restored collagen to pre-wound levels by 60 dpw. Subcutaneous IL34 enrichment at 3 dpw led to significantly increased αSMA expression at 7 and 14 dpw, a higher type I:III collagen ratio at 7 dpw, and suppression of inflammatory mediators coupled with enhancement of other, anti-inflammatory mediators at 7dpw. CSF1 enrichment had no significant effect on αSMA expression or subsequent collagen deposition, but did show a bias towards inflammatory mediators and the suppression of resolving and pro-reparative transcripts at 7 dpw. These findings suggest that early IL34 supplementation promotes a pro-regenerative macrophage phenotype that enhances myofibroblast activation and matrix remodeling while early CSF1 supplementation may contribute to prolonged inflammation and impaired tissue regeneration. Temporal modulation of macrophage-derived signals, particularly IL34, plays a critical role in directing scarless skin regeneration in X. laevis. These findings identify a conserved immunoregulatory axis with potential relevance to improving wound healing in non-regenerative species. Xenopus laevis juvenile frogs are uniquely capable of scarless skin regeneration, but the cellular and molecular mechanisms guiding this process remain incompletely understood. Macrophages are known as key regulators of wound healing, yet how their phenotypes shift over time and influence downstream regeneration in X. laevis has not been previously defined. It is well established that M( functions are imperative to mammalian wound healing. In vertebrate biology, M( polarization is dictated by two colony-stimulating factor-1 (CSF1) receptor ligands: CSF1 and interleukin-34 (IL34). While IL34 in mammals is critical to the development of epidermal M(s known as Langerhans cells, the contribution of CSF1- and IL34-derived macrophages to skin wound repair remains unexplored. Pertinently, using the X. laevis model, previous work from our lab showed that CSF1- and IL34- M(s are functionally distinct, formulating our hypothesis that these subsets play distinct roles during different phases of cutaneous wound repair. We therefore characterized full-thickness (epidermis and dermis) skin wounds in juvenile X. laevis during regeneration, analyzing transcript levels reflecting: macrophage infiltration (csf1r) and phenotype abundance (csf1 and il34), fibroblast activation (αSMA/acta2), and wound bed collagen composition (Picrosirius red staining). To assess the functional roles of macrophage phenotypes, we enriched wounds with recombinant X. laevis CSF1, IL34, or a vector control 3 days post-wounding (dpw) and analyzed wound responses at 7 and 14 dpw. Normal scarless regeneration in these juveniles demonstrated that macrophages transiently accumulated in the wound bed, peaking at 7–14 dpw. This coincided with elevated csf1 expression, which later declined as il34 levels rose. Fibroblast activation into myofibroblasts as well as collagen deposition followed this cytokine shift and restored collagen to pre-wound levels by 60 dpw. Subcutaneous IL34 enrichment at 3 dpw led to significantly increased αSMA expression at 7 and 14 dpw, a higher type I:III collagen ratio at 7 dpw, and suppression of inflammatory mediators coupled with enhancement of other, anti-inflammatory mediators at 7dpw. CSF1 enrichment had no significant effect on αSMA expression or subsequent collagen deposition, but did show a bias towards inflammatory mediators and the suppression of resolving and pro-reparative transcripts at 7 dpw. These findings suggest that early IL34 supplementation promotes a pro-regenerative M( phenotype that enhances myofibroblast activation and matrix remodeling while early CSF1 supplementation may contribute to prolonged inflammation and impaired tissue regeneration. Temporal modulation of macrophage-derived signals, particularly IL34, plays a critical role in directing scarless skin regeneration in X. laevis. These findings identify a conserved immunoregulatory axis with potential relevance to improving wound healing in non-regenerative species.
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Project description:TNF-mediated macrophage polarization is important for inflammatory disease pathogenesis, but mechanisms that regulate polarization are not well understood. Transcriptomic and epigenomic analysis of the TNF response in primary human macrophages revealed late phase activation of SREBP2, the master regulator of cholesterol biosynthesis genes. TNF stimulation extended the genomic profile of SREBP2 occupancy to include binding to and activation of inflammatory and interferon response genes independently of its functions in sterol metabolism. Genetic ablation of SREBP function shifted the balance of macrophage polarization from M1 to an M2-like reparative phenotype in peritonitis and skin wound healing models. Genetic ablation of SREBP activity in myeloid cells or topical pharmacological inhibition of SREBP improved skin wound healing under homeostatic and chronic inflammatory conditions. Our results identify a new function and mechanism of action for SREBP2 in augmenting TNF-induced M1 macrophage polarization and inflammation, and open therapeutic avenues for promoting wound repair.
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