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Updated: Mar 27, 2026
Suppression of Pro-fibrotic Signaling Potentiates Factor-mediated Reprogramming of Mouse Embryonic Fibroblasts into Induced Cardiomyocytes
Published on: June 3, 2018
Suppression of fibroblastic activity prolongs cardiac transplant survival through targeting their ATG5 expression
Zelai Wu1, Bixian Luo2, Deqiang Kong3
1Department of Surgery, Second Affiliated Hospital of School of Medicine, Zhejiang University, Hangzhou, China; Department of Cardiovascular Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, People's Republic of China.
Insights
Targeting cardiofibroblast autophagy-related protein 5 (ATG5) in heart allografts prolonged graft survival. Suppressing ATG5 reduced inflammation and T cell proliferation, offering a novel therapeutic strategy for heart transplantation.
Area of Science:
- Cardiovascular Biology
- Transplantation Immunology
- Cellular Autophagy
Background:
- Cardiofibroblasts are implicated in ischemia and inflammation.
- Their specific role in heart transplantation remains unclear.
Purpose of the Study:
- To investigate the function of cardiofibroblasts in heart transplantation.
- To explore the role of autophagy in cardiac allograft rejection.
Main Methods:
- Performed syngeneic and allogeneic heterotopic cardiac transplantation in mice.
- Utilized qPCR, western blotting, flow cytometry, and immunofluorescence.
- Generated conditional knockout mice for autophagy-related protein 5 (ATG5) in donor myofibroblasts.
Main Results:
- Cardiac fibroblasts transformed into myofibroblasts with increased autophagy markers (ATG5, ATG7, LC3-II) in allografts.
- Conditional deletion of ATG5 in donor myofibroblasts prolonged graft survival.
- Reduced inflammatory cytokine infiltration and CD8+ T cell proliferation were observed in ATG5-deficient grafts.
- Chronic transplantation models also showed prolonged survival and reduced fibrosis with ATG5 knockout.
Conclusions:
- Suppressing cardiofibroblast activity, specifically targeting ATG5, significantly prolongs cardiac allograft survival.
- Targeting fibroblastic ATG5 represents a potential therapeutic strategy to improve heart transplant outcomes.
Background:
Cardiofibroblasts are closely involved in the process of ischemia and inflammation. Nevertheless, the role of cardiofibroblasts remains unknown in heart transplantation.
Methods:
Syngeneic and allogeneic heterotopic cardiac transplantations were performed using C57BL/6 or BALB/c donors for BALB/c recipients through different treatments. Some mice were used to observe the survival of the cardiac grafts. Quantitative polymerase chain reaction, Western blotting, flow cytometry, and immunofluorescence staining were used to identify the fibroblast function in heart grafts.
Results:
Our study revealed that cardiac fibroblasts were activated and transformed into myofibroblasts. In the myofibroblasts of heart allografts, the expression levels of ATG5, ATG7, and microtubule-associated protein light chain 3-II were increased. Conditional deletion of ATG5 in donor myofibroblasts prolonged heart graft survival, reduced infiltration of inflammatory cytokines (including interleukin-6, interleukin-1β, tumor necrosis factor-α, and interleukin-18), and inhibited CD8+ T-cell proliferation. In the myofibrillogenesis regulator 1-induced chronic cardiac transplantation model, these conditional knockout grafts also exhibited prolonged survival and reduced fibrosis.
Conclusions:
Significant prolongation of cardiac allograft survival might be achieved by suppressing the activity of cardiofibroblasts, which could be effectively regulated by targeting fibroblastic ATG5, a critical component of autophagy.
