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Macrophage-derived IL-1β controls metabolic reprograming in distinct fibroblast progenitors to determine cell fate during wound healing

ABSTRACT: Compare with facial skin, oral mucosa has a high regenerative capacity and rapid healing efficiency, which has long been recognized as an ideal system of wound resolution. To decipher the underlying molecular mechanisms fostering this optimal healing process, we created a parallel injury model for both the oral and facial skin within the same mice. Utilizing single-cell transcriptomics (scRNA-seq) analysis, we were able to illuminate the diverse cell populations and the intricate cell-to-cell interactions taking place at a single cell level. Leveraging tools such as CytoTRACE, along with cell trajectory and RNA velocity analyses, we pinpointed fibroblast progenitors. Through the employment of GSEA and CellChat analyses, corroborated by flow cytometry and immunofluorescence staining, we demonstrated that IL-1β derived from macrophages augments oxidative phosphorylation in Il1rl1+ progenitors in skin. This points to a rapid response mechanism facilitated by heightened cell-cell interactions through IL-1β signals. We elucidated that the underlying mechanism involves a metabolic reprogramming in oral Il1rl1+ fibroblast progenitors driven by IL-1β/IL1R1, triggering the activation of the NFκB signaling pathway. This shift transitions the metabolic state from glycolysis to oxidative phosphorylation, favoring stem cell differentiation over proliferation and consequently accelerating wound healing in the oral mucosa.

ORGANISM(S): Mus musculus

PROVIDER: GSE256125 | GEO | 2025/09/03

REPOSITORIES: GEO

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Project description:Wound healing is a complex process regulated by various cell types and a plethora of mediators. While interactions between wounded skin and the hair follicles (HFs) could induce HF neogenesis or promote wound healing, it remains unknown whether the wound healing-associated signaling milieu can be manipulated to protect against alopecia, such as chemotherapy-induced alopecia (CIA). Utilizing a well-established neonatal rat model of CIA, we show here that skin wounding protects from alopecia caused by several clinically relevant chemotherapeutic regimens, and that protection is dependent on the time of wounding and hair cycle stage. Gene expression profiling unveiled a significant increase in interleukin-1 beta (IL-1β) mediated signaling by skin wounding. Subsequently, we showed that IL-1β is sufficient and indispensable for mediating the CIA-protective effect. Administration of IL-1β alone to unwounded rats exhibited local CIA protection while IL-1β neutralization abrogated CIA protection by wounding. Mechanistically, IL-1β retarded postnatal HF morphogenesis, making HFs at the wound sites or IL-1β treated areas damage-resistant while the rats developed total alopecia elsewhere. We conclude that wound healing switches the cutaneous cytokine milieu to an IL-1β-dominated state thus retarding HF growth progression and rendering the HFs resistant to chemotherapy agents. In the future, manipulation of HF progression through interfering with the IL-1β signaling milieu may provide therapeutic benefits to a variety of conditions, from prevention of CIA to inhibition of hair growth and treatment of hirsutism. In this experiment, we used the Rat MI-Ready array comprised of over 34,000 transcript probes for gene and alternative splice products in ENSEMBL release 37 to profile gene expression changes during acute wound healing in rat skin. 16,198 Selected rat probes were above threshold in at least one group. 3,239 significant genes were found (FDR < 0.1).

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Macrophage-derived IL-1β controls metabolic reprograming in distinct fibroblast progenitors to determine cell fate during wound healing

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