Engineered immunosuppressive dendritic cells protect against cardiac remodelling | Nature
Subjects
- Immunosuppression
- Translational research
Abstract
Heart failure remains a leading cause of morbidity and mortality, yet no approved therapies effectively prevent or reverse pathological cardiac fibrosis and the associated decline in cardiac function1,2,3,4. Chronic inflammation is a central driver of pathological fibrosis after ischaemic or haemodynamic stress, but strategies that locally rebalance injurious and reparative immune responses without systemic immunosuppression are lacking5,6. Dendritic cells (DCs) are key regulators of immune activation and tolerance, providing an opportunity for therapeutic immune reprogramming in cardiac diseases7,8. Here we show that engineered immunosuppressive and fibrosis-targeted DCs (iCDCs) effectively protect against pathological cardiac remodelling. In mouse models of ischaemia–reperfusion injury, myocardial infarction and pressure overload, iCDC therapy reduced inflammatory cardiac fibrosis, improved cardiac perfusion and preserved contractility. Mechanistically, iCDCs conferred sustained cardioprotection directly by suppressing immune and stromal cell activation or indirectly through promoting clonal expansion of regulatory T cells. Importantly, in a non-human primate model of myocardial infarction, iCDC therapy also reduced cardiac fibrosis, improved cardiac perfusion and contractile function without inducing systemic toxicity. These findings establish lesion-targeted immune modulation as a feasible strategy to control cardiac fibrosis and identify engineered dendritic cells as a promising therapeutic platform for treating cardiac remodelling and heart failure.
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Fig. 1: Generation and in vitro functional validation of FAP-targeted immunosuppressive DCs.
Fig. 2: FAP-targeted iCDCs attenuate cardiac fibrosis and improve cardiac function after MI and I/R.
Fig. 3: Single-cell transcriptomic and TCR profiling reveals T-cell-centric immunomodulation by iCDC therapy after I/R.
Fig. 4: iCDC therapy reprograms non-T immune cells and fibroblasts after cardiac injury.
Fig. 5: iCDC therapy mitigates cardiac fibrosis and enhances functional recovery in a NHP model of MI.
Data availability
All sequencing data have been publicly deposited in the Genome Sequence Archive database (https://ngdc.cncb.ac.cn/gsa) under the accession number of PRJCA041520. All data in this study are available from the corresponding author on request. Source data are provided with this paper.
Code availability
The code used to process the data is publicly available at GitHub (https://github.com/averycheng-Hulab/iCDC).
References
- Conrad, N. et al. Temporal trends and patterns in heart failure incidence: a population-based study of 4 million individuals. Lancet 391, 572–580 (2018).
Article
PubMed
Google Scholar
- Yan, T. et al. Burden, trends, and inequalities of heart failure globally, 1990 to 2019: a secondary analysis based on the global burden of disease 2019 study. J. Am. Heart Assoc. 12, e027852 (2023).
Article
PubMed
PubMed Central
Google Scholar
- Khan, M. S. et al. Global epidemiology of heart failure. Nat. Rev. Cardiol. 21, 717–734 (2024).
Article
PubMed
Google Scholar
- Greene, S. J. et al. Worsening heart failure: nomenclature, epidemiology, and future directions: JACC review topic of the week. J. Am. Coll. Cardiol. 81, 413–424 (2023).
Article
PubMed
Google Scholar
- Adamo, L., Rocha-Resende, C., Prabhu, S. D. & Mann, D. L. Reappraising the role of inflammation in heart failure. Nat. Rev. Cardiol. 17, 269–285 (2020).
Article
PubMed
Google Scholar
- Markousis-Mavrogenis, G. et al. Immunomodulation and immunopharmacology in heart failure. Nat. Rev. Cardiol. 21, 119–149 (2024).
Article
PubMed
Google Scholar
- Sabado, R. L., Balan, S. & Bhardwaj, N. Dendritic cell-based immunotherapy. Cell Res. 27, 74–95 (2017).
Article
CAS
PubMed
Google Scholar
- Morante-Palacios, O., Fondelli, F., Ballestar, E. & Martinez-Caceres, E. M. Tolerogenic dendritic cells in autoimmunity and inflammatory diseases. Trends Immunol. 42, 59–75 (2021).
Article
CAS
PubMed
Google Scholar
- Virani, S. S. et al. Heart disease and stroke statistics—2021 update: a report from the American Heart Association. Circulation 143, e254–e743 (2021).
Article
PubMed
PubMed Central
Google Scholar
- Ambrosy, A. P. et al. The global health and economic burden of