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Войти в исследования Diabetes & metabolism journal · 2026
Fibroblast- and Macrophage-Derived Thrombospondin-1 Orchestrates the Fibroinflammatory Niche in Metabolic Dysfunction-Associated Steatohepatitis-Induced Fibrosis.
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Cho Sung Woo, Cha Jung Hoon, Seo Deok Wha, Kwon Mi Hyun, Tak Kwon Yong, Cho Hee Sun, Yang Keungmo, Jung Seo Young, Hwangbo SuHyun, Ryu Jae Yong, Bae Si Hyun, Sung Pil Soo
Аннотация
BACKGROUND: Thrombospondin-1 (THBS1) activates latent transforming growth factor-β1 (TGF-β1) and contributes to stromal- immune communication. However, how THBS1 derived from fibroblasts and macrophages collectively contributes to fibroinflammatory remodeling in metabolic dysfunction-associated steatohepatitis (MASH) has not been clearly defined.
METHODS: THBS1 expression was examined in liver tissue and serum from patients with metabolic dysfunction-associated steatotic liver disease (MASLD) and in two dietary murine MASH models. We integrated single-cell RNA sequencing, immunohistochemistry, confocal microscopy, and flow cytometry with targeted perturbation of fibroblasts and macrophages using nintedanib, the THBS1-blocking peptide LSKL, and siRNA-mediated THBS1 silencing.
RESULTS: THBS1 and the fibroblast activation marker fibroblast activation protein (FAP) increased in association with fibrosis severity and interleukin-6 (IL-6) levels. Single-cell RNA sequencing and spatial imaging demonstrated THBS1 expression in both FAP+ fibroblasts and monocyte-derived macrophages, indicating a coordinated fibroinflammatory niche. Nintedanib reduced THBS1 expression in both compartments, decreased CD11b+MERTK+ macrophages and FAP+PD-L1+ fibroblasts, and improved histologic fibrosis. Direct THBS1 inhibition produced similar antifibrotic effects. In vitro, THBS1 knockdown or blockade suppressed TGF-β1-induced fibroblast activation and reduced lipopolysaccharide-stimulated IL-1β and IL-6 production in macrophages, supporting reciprocal THBS1-dependent stromal-immune signaling.
CONCLUSION: THBS1 functions as a shared signaling mediator between fibroblasts and macrophages in MASH. Therapeutic suppression of THBS1, either through nintedanib or direct inhibition, disrupts this fibroinflammatory circuit and may represent a viable strategy to limit fibrosis progression in MASLD/MASH.
METHODS: THBS1 expression was examined in liver tissue and serum from patients with metabolic dysfunction-associated steatotic liver disease (MASLD) and in two dietary murine MASH models. We integrated single-cell RNA sequencing, immunohistochemistry, confocal microscopy, and flow cytometry with targeted perturbation of fibroblasts and macrophages using nintedanib, the THBS1-blocking peptide LSKL, and siRNA-mediated THBS1 silencing.
RESULTS: THBS1 and the fibroblast activation marker fibroblast activation protein (FAP) increased in association with fibrosis severity and interleukin-6 (IL-6) levels. Single-cell RNA sequencing and spatial imaging demonstrated THBS1 expression in both FAP+ fibroblasts and monocyte-derived macrophages, indicating a coordinated fibroinflammatory niche. Nintedanib reduced THBS1 expression in both compartments, decreased CD11b+MERTK+ macrophages and FAP+PD-L1+ fibroblasts, and improved histologic fibrosis. Direct THBS1 inhibition produced similar antifibrotic effects. In vitro, THBS1 knockdown or blockade suppressed TGF-β1-induced fibroblast activation and reduced lipopolysaccharide-stimulated IL-1β and IL-6 production in macrophages, supporting reciprocal THBS1-dependent stromal-immune signaling.
CONCLUSION: THBS1 functions as a shared signaling mediator between fibroblasts and macrophages in MASH. Therapeutic suppression of THBS1, either through nintedanib or direct inhibition, disrupts this fibroinflammatory circuit and may represent a viable strategy to limit fibrosis progression in MASLD/MASH.