| 著者 |
Weihua Gong, Zelai Wu, Bixian Luo, Deqiang Kong, Xiaolong Miao, Hongming Liu, Weixun Xie, Chengyu Hu, Jun He, Dong Cao, Zhonghua Shen, Minjian Kong, Aiqiang Dong, Bing-Feng Shi
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| Abstract |
Background
Fibrobalst plays a critical role in heart physiology and pathology, yet their immunological role in transplanted heart grafts remains unclear, particularly the mechanisms involved.
Methods
Heart transplantation was performed in mouse models (C57BL/6J, BALB/c, PostnMCM, Rosa26-tdTomato, and ATG5floxp/floxp). Single-cell RNA sequencing, qPCR, western blotting, flow cytometry, and immunofluorescence staining were used to identify fibroblast subpopulations and assess their immunological functions.In vivo and in vitro assays explored the mechanisms of MHC molecule expression.
Results
Using scRNA-seq, qPCR, western blotting, flow cytometry, and immunofluorescence staining, we identified three distinct cardiac fibroblast subpopulations in heart grafts, including silent fibroblasts, myofibroblasts, and MHChigh fibroblasts. Activation and MHC molecule expression in cardiac fibroblasts were found to be dependent on IFN-γ both in vivo and in vitro.Genetic lineage tracing revealed that myofibroblasts exhibit higher MHC class I expression, which appears to be mediated by the expression of periostin (Postn). Differential gene expression analysis between myofibroblasts and MHChigh fibroblasts indicated upregulation of the autophagy signaling pathway. Furthermore, diminished MHC class I expression was observed in ATG5-deficient fibroblasts in vitro. Conditional deletion of ATG5 in myofibroblasts using the Cre/floxp system led to prolonged heart graft survival, reduced infiltration of inflammatory cytokines as well as chemokines, and decreased CD8 + T cell proliferation.
Conclusion
This study suggests that cardiac fibroblasts, particularly myofibroblasts, enhance antigen presentation via autophagy signaling during heart transplantation. These findings give valuable insights into underlying therapeutic targets for heart graft survival.
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