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 function1–4.
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 function. 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 lacking.
Dendritic cells are key regulators of immune activation and tolerance, providing an opportunity for therapeutic immune reprogramming in cardiac diseases. Here we show that engineered immunosuppressive and fibrosis-targeted DCs 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.Fig. 1: Generation and in vitro functional validation of FAP-targeted immunosuppressive DCs.Fig. 3: Single-cell transcriptomic and TCR profiling reveals T-cell-centric immunomodulation by iCDC therapy after I/R.PRJCA041520Yan, 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.Ambrosy, A. P. et al. The global health and economic burden of hospitalizations for heart failure: lessons learned from hospitalized heart failure registries.Jones, N. R., Roalfe, A. K., Adoki, I., Hobbs, F. D. R. & Taylor, C. J. Survival of patients with chronic heart failure in the community: a systematic review and meta-analysis.Cohn, J. N., Ferrari, R. & Sharpe, N. Cardiac remodeling—concepts and clinical implications: a consensus paper from an international forum on cardiac remodeling.Frantz, S., Hundertmark, M. J., Schulz-Menger, J., Bengel, F. M. & Bauersachs, J. Left ventricular remodelling post-myocardial infarction: pathophysiology, imaging, and novel therapies.Mann, D. L. The emerging role of innate immunity in the heart and vascular system: for whom the cell tolls.Murphy, S. P., Kakkar, R., McCarthy, C. P. & Januzzi, J. L. Jr. Inflammation in heart failure: JACC state-of-the-art review.Google ScholarBalaji, S. et al. Interleukin-10-mediated regenerative postnatal tissue repair is dependent on regulation of hyaluronan metabolism via fibroblast-specific STAT3 signaling.Google Scholar Hu, X. et al. A large-scale investigation of hypoxia-preconditioned allogeneic mesenchymal stem cells for myocardial repair in nonhuman primates: paracrine activity without remuscularization.Li, G. et al. Dynamic molecular atlas of cardiac fibrosis at single-cell resolution shows CD248 in cardiac fibroblasts orchestrates interactions with immune cells.Ackers-Johnson, M. et al. A simplified, Langendorff-free method for concomitant isolation of viable cardiac myocytes and nonmyocytes from the adult mouse heart. We thank Y. Wang for discussion; and T. Lin, Y. Li, T. Lu, Y. Wang and L. Wang for technical support. This work was supported by National Science Fund for Distinguished Young Scholars , grants from National Key Research and Development Program of China , the Key Project of National Natural Science Foundation of China , Leading Innovative and Entrepreneur Team Introduction Program of Zhejiang , the Project for Central-Guided Regional Science and Technology Development , the Key research and development program of Zhejiang Province and the Fundamental Research Funds for the Central Universities .Department of Cardiology, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China Xiaoying Li, Jiamin Li, Guohua Li, Guo Cheng, Huanqiang Li, Hao Lin, Ningqing Jia, Xiaoqian Hong, Ye Liu, Zhiwei Zhong, Yize Chen, Biqing Wang, Jing Zhao, Zhenqi Hua, Lingjun Wang, Qiming Chen, Peijie Zheng, Shuyuan Sheng, Songting Gu, Cheng Ni, Shuchang Ye, Changle Ke, Feimu Zhang, Mo Li, Junhua He, Yan Wu, Yinghui Xu, Huajun Li, Yu Zhang, Guanhua Hu, Chengchen Zhao, Yang Xu & Xinyang HuXiaoying Li, Guohua Li, Huanqiang Li, Hao Lin, Ningqing Jia, Xiaoqian Hong, Jing Zhao, Zhenqi Hua, Qiming Chen, Peijie Zheng, Yan Wu, Yang Xu & Xinyang HuXiaoying Li, Guohua Li, Huanqiang Li, Hao Lin, Ningqing Jia, Xiaoqian Hong, Jing Zhao, Zhenqi Hua, Qiming Chen, Peijie Zheng, Yan Wu, Yang Xu & Xinyang HuXiaoying Li, Guo Cheng, Lingjun Wang, Yang Xu & Xinyang HuX.L., J.L., G.L., Huanqiang Li, H. Lin, L.Z., N.J., X. Hong, Z.H., L.W., Qiming Chen, P.Z., S. Sheng, Y.C., S.G., Y.Z., G.H. and L.Y. performed mouse surgeries and subsequent downstream experiments. X.L., L.Z. and Huanqiang Li generated the lentiviral construct and lentivirus, and engineered DCs and conducted in vitro assays. M.K., Qi Chen and C.K. established the MI model in NHPs. Huajun Li and Y.D. performed cardiac echocardiography assessments in NHPs. J.S. and C.Z. conducted MRI analyses in NHPs. J.L., Huanqiang Li, J.Z. Y.C. and L.Z. carried out western blot experiments. J.L., H. Lin and S.Y. performed Sirius Red staining and image analysis. J.L., H. Lin, Z.Z., S. Sheng, S.Y., F.Z. and J.H. conducted immunofluorescence staining and data quantification. G.C., M.L. and S. Shi performed scRNA-seq and spatial transcriptomic analyses. Y.L., B.W., Y.W. and Yinghui Xu organized and analysed the data. X.L., J.L., G.L., Huanqiang Li and C.N. interpreted the data and contributed to experimental design and manuscript revision. Yand Xu and X. Hu conceived the study, supervised the project, interpreted the data, and drafted and edited the manuscript. All of the authors read and approved the final version of the manuscript.thanks Betul Gunes, Kevin King, Louai Labanieh and the other, anonymous, reviewer for their contribution to the peer review of this work. , Schematic of the lentiviral construct encoding a fibroblast activation protein -specific chimeric antigen receptor composed of an anti-FAP scFv, murine CD8α hinge/transmembrane domains, and IRES-linked immunomodulatory payloads: CTLA4-Ig, PD-L1, and IL-10., ELISA quantification of IL-10 and CTLA4-Ig secretion from DC culture supernatants, showing significantly elevated production in iCDCs compared to WTDC and VecDC. n = 3 biological replicates per group.) T cell subsets in in vitro CD3/CD28-activated T cells cocultured with or without iCDCs in the presence or absence of neutralizing antibodies against IL-10, CTLA4, or PD-L1 . Data are presented as mean ± s.e.m.; hypergeometric test , day 3 or day 7 . n = 8 mice in iCDC and iCDC , n = 9 mice in other three groups.) iCDC therapy after I/R. Representative echocardiograms, functional quantification and fibrosis analysis are shown. Sham, n = 7 mice; I/R, n = 11 mice; iCDC Low, n = 10 mice; iCDC High, n = 11 mice; fibrosis, n = 6 mice per group. Scale bar, 2 mm., Representative M-mode echocardiograms and quantification of LVIDd and LVIDs at day 3 and day 28 post-MI. n = 10 mice in Sham group, and n = 15 mice in other four groups., Kaplan-Meier survival curves for MI mice treated with VecDC or iCDC. n = 29 mice in MI group, and n = 25 mice in VecDC and iCDC groups., Representative M-mode echocardiograms and quantification of LVIDd and LVIDs at 3 days, 4 weeks, 8 weeks, and 12 weeks post-I/R. Sham, n = 8 mice; I/R, n = 11 mice; VecDC, n = 10 mice; iCDC, n = 10 mice., Immunofluorescence and transcriptomic analyses showing enhanced angiogenesis in iCDC-treated hearts. Data are shown as mean ± s.e.m. , FAP scFv+IL-10 + CTLA4-Ig , FAP scFv+IL-10 + PD-L1 , and fully engineered iCDCs., Representative M-mode echocardiogram images and quantitative assessment of cardiac function at days 3 and 28 post-MI, including EF%, FS%, LVIDd and LVIDs. n = 10 mice in Sham group, and n = 15 mice in other five groups., Sirius Red staining and quantification of fibrotic area at day 28 post-MI in Sham , MI , FAP-CP , FAP-CI , FAP-PI , and iCDC groups. Scale bar, 2 mm., Western-blot analysis of fibronectin, periostin, and α-SMA in heart tissues with quantification normalized to β-actin ., Flow cytometry validation of FAP scFv expression in cultured dendritic cells expressing single immunomodulatory factor retaining FAP scFv, including FAP scFv+CTLA4-Ig , FAP scFv+PD-L1 , FAP scFv+IL-10 and iCDCs., Representative M-mode echocardiograms and functional quantification at days 3 and 28 post-MI. n = 10 mice in Sham group, and n = 15 mice in other five groups., Sirius Red staining and fibrosis quantification at 4 weeks post-MI in Sham , MI , FAP-C , FAP-P , FAP-I , and iCDC groups. Scale bar, 2 mm., Western-blot analysis of fibronectin, periostin, and α-SMA in heart tissues from Sham, MI, FAP-C, FAP-P, FAP-I, and iCDC groups, with quantification normalized to β-actin . Data are presented as mean ± s.e.m., except for, Ex vivo bioluminescence imaging of hearts after intravenous infusion of DiR-labelled iCDCs, vector-only DCs , DCs expressing CTLA4-Ig, PD-L1 and IL-10 without FAP scFv , and DCs expressing GFP-specific scFv, CTLA4-Ig, PD-L1 and IL-10 in the TAC model. Right, signal quantification ., Experimental timeline showing intravenous administration of iCDCs at 4 and 6 weeks post-TAC, with echocardiographic and histological analyses at 4, 6 and 8 weeks., Echocardiographic assessment demonstrating improved ejection fraction and fractional shortening in iCDC-treated mice. Sham, n = 11 mice; TAC, n = 10 mice; TAC+VecDC, n = 9 mice; TAC+iCDC, n = 8 mice., Sirius Red staining of cardiac sections at 8 weeks post-TAC showing reduced interstitial fibrosis with iCDC treatment; right, fibrosis quantification. Sham , TAC , VecDC , iCDC . Scale bars, 1 mm and 50 μm ., Echocardiographic evaluation showing improved EF% and FS% at 2 and 4 weeks after iCDC treatment in mice with baseline EF< 40%. n = 8 mice in Sham, n = 10 mice in other three groups., Sirius Red staining and fibrosis quantification at 8 weeks post-TAC. n = 6 mice in iCDC, n = 5 mice in other three groups. Scale bars, 1 mm and 50 μm ., Western blot analysis of fibrotic markers in hearts from Sham, TAC, TAC+VecDC and TAC+iCDC groups .endothelial cells showing increased vessel density after iCDC treatment. n = 6 mice in iCDC, n = 5 mice in other three groups. Scale bar, 500 μm and 100 μm ., Kaplan–Meier survival curves of TAC mice with baseline EF< 40%. n = 11 mice in iCDC, n = 12 mice in other two groups. Data are presented as mean ± s.e.m., except for, Western blot analysis of FAP protein expression in cardiac tissue at 2, 4, 6, and 8 weeks after transverse aortic constriction , with quantification shown ., Ex vivo fluorescence imaging of major organs after infusion of DiR-labelled WTDC, vector-only DCs , DCs expressing CTLA4-Ig, PD-L1 and IL-10 without FAP scFv , and DCs expressing GFP-specific scFv, CTLA4-Ig, PD-L1 and IL-10 , and iCDC at 1 day, 3 days, 7 days and 14 days post-injection, with quantification shown in, Quantification of left ventricular internal dimensions in diastole and systole at 4 weeks, 6 weeks, and 8 weeks post-TAC across the indicated groups. Sham , TAC , VecDC , iCDC .endothelial cells in the indicated treatment groups. iCDC treatment markedly enhances capillary density. Sham , TAC , VecDC , iCDC . Scale bars, 500 μm and 100 μm ., LVIDd and LVIDs measurements at baseline , and 2 weeks and 4 weeks post-therapy in mice with pre-existing heart failure. n = 8 mice in Sham, n = 10 mice in other three groups. Data are presented as mean ± s.e.m., except for, Quantification of non-sustained VT episodes and duration, sustained VT episodes and duration, and PVCs numbers in MI mice treated with or without iCDC ., H&E staining of lung, kidney, and liver tissues from Sham, MI, VecDC-, CPI-DC, and iCDC-treated groups at 28 days post-MI. Scale bar, 100 μm., Representative hematoxylin and eosin staining of lung, kidney, and liver tissues from Sham, I/R, VecDC-, and iCDC-treated mice at 28 days post-I/R injury. Scale bar, 100 μm., Serum biochemical analysis of liver and kidney function markers including alanine aminotransferase , aspartate aminotransferase , blood urea nitrogen , and creatinine . n = 5 mice in VecDC, n = 6 mice in other three groups., H&E staining of lung, kidney, and liver from Sham, TAC, VecDC-, and iCDC-treated mice at 28 days post-TAC surgery. Scale bar, 100 μm., Corresponding serum biochemical assessment in the TAC model shows comparable values across groups. Sham , TAC , VecDC , iCDC ., Serum cytokine levels measured by ELISA, including IFN-γ, IL-6, TNF-α, IL-17A, IL-4, and IL-10. iCDC treatment significantly reduced pro-inflammatory cytokines compared to I/R controls . Data are presented as mean ± s.e.m., except for, Gene Ontology enrichment analysis of upregulated and downregulated biological processes in iCDC-treated hearts compared to VecDC-treated controls. iCDC n = 6 mice, VecDC n = 4 mice., KEGG enrichment analysis of upregulated and downregulated genes comparing iCDC versus VecDC-treated groups. These results indicate that iCDC treatment attenuates pro-inflammatory and fibrotic signalling while promoting pathways associated with cardiac structural and metabolic recovery. Extended Data Fig. 8 Single-Cell RNA Sequencing and flow cytometry reveal iCDC-mediated reprogramming of cardiac T cells following I/R injury. , Dot plot showing expression of representative marker genes across major cardiac immune cell subsets, including macrophage, dendritic cells, neutrophils, B cells, T cells, and natural killer cells, and fibroblasts and endothelial cells., Dot plot displaying top marker genes across identified T cell subtypes, including T helper , cytotoxic T , γδ T cells , regulatory T cells , naive T cells, central memory T cells , and immature T cells., GO and KEGG enrichment analysis of downregulated pathways in cardiac T cells from iCDC-treated versus I/R control mice, revealing the suppression of pathways associated with T cell proliferation and activation ., Flow cytometric analysis of cardiac T cells from Sham, I/R, VecDC, and iCDC-treated mice, assessing the frequency of total CD3Tregs at day 7 and day 28 post-MI, assessing CD69, CD44, and CD62L expression to evaluate activation and memory differentiation .T cells at day 7 post-MI. UMAP projection identifies seven transcriptionally distinct T-cell clusters; stacked bar plots show relative cluster proportions in heart and blood; dot plots display representative marker genes. Extended Data Fig. 9 Single-Cell RNA Sequencing reveals iCDC-mediated transcriptional modulation of cardiac macrophages and dendritic cells following ischaemia/reperfusion injury. , Dot plot showing top marker genes across identified cardiac myeloid subsets, including the subpopulations of macrophage, monocytes, and dendritic cells ., Gene Ontology and KEGG pathway enrichment analysis of downregulated genes in macrophages following iCDC treatment versus I/R alone . Pathways involved in phagocytosis, cytokine production, and antigen presentation were significantly suppressed. The heatmap shows expression of representative downregulated genes associated with phagocytosis, antigen processing and presentation, and pro-inflammation in macrophages across Sham, I/R, and iCDC groups., Flow cytometry analysis of cardiac macrophages across treatment groups , showing changes in the expression of macrophage markers CCR2, MHCII, and TIM4., GO and KEGG enrichment analysis of downregulated genes in dendritic cells from iCDC-treated versus I/R control hearts, highlighting reduced expression in pathways related to antigen processing, endocytosis, and inflammatory signalling . Accompanying heatmap displays expression of representative suppressed genes associated with antigen processing and presentation, immune activation, and pro-inflammation., GO and KEGG enrichment analysis of upregulated genes in dendritic cells from iCDC-treated versus I/R control hearts . Enriched pathways include those related to immune regulation, cell adhesion, and tissue repair. Heatmap at right illustrates increased expression of representative genes associated with cell adhesion, cell migration and anti-inflammation in iCDC-treated hearts. Extended Data Fig. 10 Single-Cell RNA Sequencing and flow cytometry analysis of neutrophils and B cells in response to iCDC treatment., Gene Ontology and KEGG pathway enrichment analysis of genes downregulated in cardiac neutrophils from iCDC-treated versus I/R control hearts, revealing inhibition of inflammatory responses, LPS sensing, and neutrophil chemotaxis . Accompanying heatmap displays representative downregulated genes associated with chemotaxis/migration and pro-inflammation., Flow cytometry analysis of cardiac neutrophils across treatment groups , showing changes in neutrophil proportion and its expression of ICAM-1 and CD14. iCDC treatment reduces the frequency of CD14, GO and KEGG enrichment analysis of downregulated genes in B cells from iCDC-treated hearts versus I/R controls, highlighting suppression of B cell activation, immunoglobulin production, and ERK signalling pathways ., Flow cytometry analysis of cardiac B cells across treatment groups . Representative plots show decreased expression of activation markers CD69, CD80, and IgG in B cells from iCDC-treated hearts, indicating suppressed B cell activation. , UMAP visualization of 139,036 single cells isolated from murine hearts post-I/R, clustered into 18 major cell types including fibroblasts, endothelial cells, macrophages, monocytes, dendritic cells, neutrophils, T cells, B cells, and natural killer cells., GO and KEGG enrichment of downregulated genes in cardiac fibroblasts from iCDC-treated versus I/R control hearts, including pathways related to extracellular matrix organization, cell-substrate adhesion, and wound healing ., ECM regulator score of F-Myo fibroblasts across Sham, I/R, VecDC, and iCDC-treated groups shows significant downregulation in the iCDC group. n = 3 pooled samples from 9 animals., ECM regulator scores across different subtypes of cardiac fibroblasts. F-Myo n = 7461, F-Act n = 7381, F-SH n = 18467, F-IFNs n = 922, F-SL n = 37945, F-IR n = 719 fibroblasts.expression in fibroblasts co-cultured with WTDC, VecDC, or iCDC . Data are presented as mean ± s.e.m; all statistical tests are two-sided; Wilcoxon test , vector control DCs , and FAP-targeted iCDCs, showing the expression of co-stimulatory molecules ., Quantification of end-systolic volume and end-diastolic volume by MRI at baseline baseline , day 2 , 1 month , and 3 months . n = 7 primates in MI, n = 10 primates in iCDC. Data are presented as mean ± s.e.m., Haematological parameters-including white blood cell count , platelet count , and haemoglobin levels-as well as liver and kidney function markers, including albumin/globulin ratio, alanine aminotransferase , aspartate aminotransferase , and creatinine , were assessed at baseline , and at 2, 4, 7, and 14 days, as well as 1, 2, and 3 months post-MI in both MI and iCDC-treated groups. No significant differences in WBC, PLT, haemoglobin levels, A/G, ALT, AST, and Cr were observed between the groups over time. n = 7 primates in MI, n = 10 primates in iCDC., Circulating cytokine levels of IL-6, IL-10, IL-17A, and IFN-γ were assessed pre-MI, post-MI , and at 4, 7, and 14 days post-MI. n = 7 primates in MI, n = 10 primates in iCDC., Representative hematoxylin and eosin staining of major organs including liver, lung, colon, intestine, kidney, spleen, brain, skin, and thyroid collected at 3 months post-MI in MI and iCDC-treated animals. No overt histopathological abnormalities were observed in the iCDC group., Representative brain magnetic resonance imaging scans from MI and iCDC-treated animals at 3 months post-MI, showing comparable brain morphology between groups., Quantification of non-sustained VT episodes and durations, and PVC counts in each non-human primate treated with or without iCDC daily during the 28-day monitoring. Data are presented as mean ± s.e.m., except for WBC, PLT, AST and Cr inSupplementary Fig. 1 and Supplementary Tables 1 and 2. Supplemental Fig. 1: uncropped protein gel image. Supplementary Table 1: antibody catalogue. Supplementary Table 2: RT–qPCR primer sequences. Springer Nature or its licensor holds exclusive rights to this article under a publishing agreement with the author or other rightsholder; author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
United States Latest News, United States Headlines
Similar News:You can also read news stories similar to this one that we have collected from other news sources.
Kids with heart defects soar on zip lines at University Health Kids Heart CampSAN ANTONIO - Kids battling some very serious health dificulties got the chance toTwo dozen children born with heart defects spent Saturday trying out the kind
Read more »
Heart-stopping moment rescuers swoop in on man trying to jump from LA overpassToday's Video Headlines: 4/11/2026
Read more »
3 diet tweaks heart health nutrition scientist made to prevent diseaseBusiness Insider tells the global tech, finance, stock market, media, economy, lifestyle, real estate, AI and innovative stories you want to know.
Read more »
Engineered wood converts sunlight into heat, supplies solar power even in darknessSolar panels are outdated. This wood-enabled solar system captures over 90 percent of sunlight and produces electricity on demand.
Read more »
One woman, three autoimmune diseases: CAR-T therapy vanquishes ultra-rare disease trioFourteen months after treatment with engineered immune cells, the recipient has no symptoms and doesn’t need to take medication. Fourteen months after treatment with engineered immune cells, the recipient has no symptoms and doesn’t need to take medication.
Read more »
Tumour trap: engineered enhancer sequences enlisted to kill cancer cellsNew cancer therapies are needed that do not harm healthy tissue. An engineered DNA sequence shows promise as one of the tools in a method to target brain tumour cells. New cancer therapies are needed that do not harm healthy tissue. An engineered DNA sequence shows promise as one of the tools in a method to target brain tumour cells.
Read more »