{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T19:47:35Z","timestamp":1792784855352,"version":"4.5.0"},"reference-count":38,"publisher":"Springer Science and Business Media LLC","issue":"11","license":[{"start":{"date-parts":[[2024,11,7]],"date-time":"2024-11-07T00:00:00Z","timestamp":1730937600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2024,11,7]],"date-time":"2024-11-07T00:00:00Z","timestamp":1730937600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82025029, 82150114"],"award-info":[{"award-number":["82025029, 82150114"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["32230036 and 82025002"],"award-info":[{"award-number":["32230036 and 82025002"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Grants from the Fundamental Research Funds for the Central Universities, and Strategic Pilot Science and Technology Project of Chinese Academy of Science"},{"name":"Jiangsu Funding Program for Excellent Postdoctoral Talen"},{"DOI":"10.13039\/501100002858","name":"China Postdoctoral Science Foundation","doi-asserted-by":"publisher","award":["2023M730741"],"award-info":[{"award-number":["2023M730741"]}],"id":[{"id":"10.13039\/501100002858","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Cell Death Dis"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    The function of PD-1\/PD-L1 axis have been intensively studied for immune escape of various cancers. However, the underlying function of PD-L2 remains poorly understood. Here, we demonstrate that PD-L2 is majorly expressed in exosomes with surface localization by clear cell renal cell carcinoma (ccRCC) cells. Tumor cell-derived exosome PD-L2 (TDE-PD-L2) exhibits high expression compared with TDE-PD-L1 in various cancers. In the absence of adaptive immune, TDE-PD-L2 suppresses tumor growth and metastasis. Under immune competence condition, TDE-PD-L2 is hijacked by immune cells in a PD-1-dependent manner to systematically dampen function of T cells via the increased proportion of the regulatory T cells and the decreased proportion of cytotoxic CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cells in both tumor-infiltrating T cells and spleen. The effects of TDE-PD-L2 on tumor is restored by antibodies targeting PD-L2. Collectively, we demonstrate that PD-1\/TDE-PD-L2 axis systematically suppresses T cell functions, representing a potentially therapeutic strategy for ccRCC treatment.\n                  <\/jats:p>","DOI":"10.1038\/s41419-024-07191-7","type":"journal-article","created":{"date-parts":[[2024,11,7]],"date-time":"2024-11-07T08:03:16Z","timestamp":1730966596000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":33,"title":["PD-L2 of tumor-derived exosomes mediates the immune escape of cancer cells via the impaired T cell function"],"prefix":"10.1038","volume":"15","author":[{"given":"Tongfeng","family":"Liu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuwen","family":"Cheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bo","family":"Peng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haojing","family":"Zang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-1745-2271","authenticated-orcid":false,"given":"Xiaofeng","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuetong","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xujie","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9825-5447","authenticated-orcid":false,"given":"Yinmin","family":"Gu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yongbo","family":"Pan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8177-7641","authenticated-orcid":false,"given":"Hongbo","family":"Hu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0262-4549","authenticated-orcid":false,"given":"Shan","family":"Gao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,11,7]]},"reference":[{"key":"7191_CR1","doi-asserted-by":"publisher","first-page":"252","DOI":"10.1038\/nrc3239","volume":"12","author":"DM Pardoll","year":"2012","unstructured":"Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer. 2012;12:252\u201364.","journal-title":"Nat Rev Cancer"},{"key":"7191_CR2","doi-asserted-by":"publisher","first-page":"550","DOI":"10.3389\/fimmu.2016.00550","volume":"7","author":"K Bardhan","year":"2016","unstructured":"Bardhan K, Anagnostou T, Boussiotis VA. The PD1:PD-L1\/2 pathway from discovery to clinical implementation. Front Immunol. 2016;7:550.","journal-title":"Front Immunol"},{"key":"7191_CR3","doi-asserted-by":"publisher","first-page":"137","DOI":"10.1016\/j.semcancer.2022.03.014","volume":"86","author":"S Gaikwad","year":"2022","unstructured":"Gaikwad S, Agrawal MY, Kaushik I, Ramachandran S, Srivastava SK. Immune checkpoint proteins: signaling mechanisms and molecular interactions in cancer immunotherapy. Semin Cancer Biol. 2022;86:137\u201350.","journal-title":"Semin Cancer Biol"},{"key":"7191_CR4","doi-asserted-by":"publisher","first-page":"1313","DOI":"10.1002\/jcp.27172","volume":"234","author":"FK Dermani","year":"2019","unstructured":"Dermani FK, Samadi P, Rahmani G, Kohlan AK, Najafi R. PD-1\/PD-L1 immune checkpoint: potential target for cancer therapy. J Cell Physiol. 2019;234:1313\u201325.","journal-title":"J Cell Physiol"},{"key":"7191_CR5","doi-asserted-by":"publisher","first-page":"1069","DOI":"10.1158\/2159-8290.CD-18-0367","volume":"8","author":"SC Wei","year":"2018","unstructured":"Wei SC, Duffy CR, Allison JP. Fundamental mechanisms of immune checkpoint blockade therapy. Cancer Discov. 2018;8:1069\u201386.","journal-title":"Cancer Discov"},{"key":"7191_CR6","doi-asserted-by":"publisher","first-page":"660","DOI":"10.1038\/s41422-020-0343-4","volume":"30","author":"X He","year":"2020","unstructured":"He X, Xu C. Immune checkpoint signaling and cancer immunotherapy. Cell Res. 2020;30:660\u20139.","journal-title":"Cell Res"},{"key":"7191_CR7","doi-asserted-by":"publisher","first-page":"287","DOI":"10.1038\/s41571-022-00601-9","volume":"19","author":"H Yamaguchi","year":"2022","unstructured":"Yamaguchi H, Hsu JM, Yang WH, Hung MC. Mechanisms regulating PD-L1 expression in cancers and associated opportunities for novel small-molecule therapeutics. Nat Rev Clin Oncol. 2022;19:287\u2013305.","journal-title":"Nat Rev Clin Oncol"},{"key":"7191_CR8","doi-asserted-by":"publisher","first-page":"3239","DOI":"10.1007\/s00018-020-03737-y","volume":"78","author":"Z Chi","year":"2021","unstructured":"Chi Z, Lu Y, Yang Y, Li B, Lu P. Transcriptional and epigenetic regulation of PD-1 expression. Cell Mol Life Sci. 2021;78:3239\u201346.","journal-title":"Cell Mol Life Sci"},{"key":"7191_CR9","doi-asserted-by":"publisher","DOI":"10.1002\/advs.201901779","volume":"6","author":"F Xie","year":"2019","unstructured":"Xie F, Zhou X, Fang M, Li H, Su P, Tu Y, et al. Extracellular vesicles in cancer immune microenvironment and cancer immunotherapy. Adv Sci (Weinh). 2019;6:1901779.","journal-title":"Adv Sci (Weinh)"},{"key":"7191_CR10","doi-asserted-by":"crossref","unstructured":"Th\u00e9ry C, Witwer KW, Aikawa E, Alcaraz MJ, Anderson JD, Andriantsitohaina R, et al. Minimal information for studies of extracellular vesicles 2018 (MISEV2018): a position statement of the International Society for Extracellular Vesicles and update of the MISEV2014 guidelines. J Extracell Vesicles. 2018;7:1535750.","DOI":"10.1080\/20013078.2018.1461450"},{"key":"7191_CR11","doi-asserted-by":"publisher","first-page":"617","DOI":"10.1038\/s41571-018-0036-9","volume":"15","author":"R Xu","year":"2018","unstructured":"Xu R, Rai A, Chen M, Suwakulsiri W, Greening DW, Simpson RJ. Extracellular vesicles in cancer\u2014implications for future improvements in cancer care. Nat Rev Clin Oncol. 2018;15:617\u201338.","journal-title":"Nat Rev Clin Oncol"},{"key":"7191_CR12","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-024-53561-2","volume":"15","author":"X Wang","year":"2024","unstructured":"Wang X, Liu T, Li Y, Ding A, Zhang C, Gu Y, et al. A splicing isoform of PD-1 promotes tumor progression as a potential immune checkpoint. Nat. Commun. 2024;15:9114.","journal-title":"Nat. Commun"},{"key":"7191_CR13","doi-asserted-by":"publisher","first-page":"923","DOI":"10.1158\/0008-5472.CAN-20-1619","volume":"81","author":"Y Gu","year":"2021","unstructured":"Gu Y, Niu S, Wang Y, Duan L, Pan Y, Tong Z, et al. DMDRMR-mediated regulation of m(6)A-modified CDK4 by m(6)A reader IGF2BP3 drives ccRCC progression. Cancer Res. 2021;81:923\u201334.","journal-title":"Cancer Res"},{"key":"7191_CR14","doi-asserted-by":"publisher","DOI":"10.1038\/s41419-022-04898-3","volume":"13","author":"Y Zhu","year":"2022","unstructured":"Zhu Y, Liu X, Wang Y, Pan Y, Han X, Peng B, et al. DMDRMR promotes angiogenesis via antagonizing DAB2IP in clear cell renal cell carcinoma. Cell Death Dis. 2022;13:456.","journal-title":"Cell Death Dis"},{"key":"7191_CR15","doi-asserted-by":"publisher","first-page":"771","DOI":"10.1038\/nrm3902","volume":"15","author":"JK Mouw","year":"2014","unstructured":"Mouw JK, Ou G, Weaver VM. Extracellular matrix assembly: a multiscale deconstruction. Nat Rev Mol Cell Biol. 2014;15:771\u201385.","journal-title":"Nat Rev Mol Cell Biol"},{"key":"7191_CR16","doi-asserted-by":"publisher","first-page":"158","DOI":"10.1038\/s41577-021-00566-3","volume":"22","author":"AM Gocher","year":"2022","unstructured":"Gocher AM, Workman CJ, Vignali DAA. Interferon-gamma: teammate or opponent in the tumour microenvironment? Nat Rev Immunol. 2022;22:158\u201372.","journal-title":"Nat Rev Immunol"},{"key":"7191_CR17","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-022-32899-5","volume":"13","author":"BP Hurrell","year":"2022","unstructured":"Hurrell BP, Helou DG, Howard E, Painter JD, Shafiei-Jahani P, Sharpe AH, et al. PD-L2 controls peripherally induced regulatory T cells by maintaining metabolic activity and Foxp3 stability. Nat Commun. 2022;13:5118.","journal-title":"Nat Commun"},{"key":"7191_CR18","doi-asserted-by":"publisher","first-page":"961","DOI":"10.1007\/s10120-020-01079-z","volume":"23","author":"Y Nakayama","year":"2020","unstructured":"Nakayama Y, Mimura K, Kua LF, Okayama H, Min AKT, Saito K, et al. Immune suppression caused by PD-L2 expression on tumor cells in gastric cancer. Gastric Cancer. 2020;23:961\u201373.","journal-title":"Gastric Cancer"},{"key":"7191_CR19","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1186\/s13578-019-0282-2","volume":"9","author":"Y Zhang","year":"2019","unstructured":"Zhang Y, Liu Y, Liu H, Tang WH. Exosomes: biogenesis, biologic function and clinical potential. Cell Biosci. 2019;9:19.","journal-title":"Cell Biosci"},{"key":"7191_CR20","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1038\/ncb2000","volume":"12","author":"M Ostrowski","year":"2010","unstructured":"Ostrowski M, Carmo NB, Krumeich S, Fanget I, Raposo G, Savina A, et al. Rab27a and Rab27b control different steps of the exosome secretion pathway. Nat Cell Biol. 2010;12:19\u201330.","journal-title":"Nat Cell Biol"},{"key":"7191_CR21","doi-asserted-by":"publisher","first-page":"1584","DOI":"10.1016\/j.yexcr.2008.09.020","volume":"315","author":"MS Pols","year":"2009","unstructured":"Pols MS, Klumperman J. Trafficking and function of the tetraspanin CD63. Exp Cell Res. 2009;315:1584\u201392.","journal-title":"Exp Cell Res"},{"key":"7191_CR22","doi-asserted-by":"crossref","unstructured":"Cao Z, Kon N, Liu Y, Xu W, Wen J, Yao H, et al. An unexpected role for p53 in regulating cancer cell-intrinsic PD-1 by acetylation. Sci Adv. 2021;7:eabf4148.","DOI":"10.1126\/sciadv.abf4148"},{"key":"7191_CR23","doi-asserted-by":"publisher","first-page":"6640","DOI":"10.1073\/pnas.1921445117","volume":"117","author":"X Wang","year":"2020","unstructured":"Wang X, Yang X, Zhang C, Wang Y, Cheng T, Duan L, et al. Tumor cell-intrinsic PD-1 receptor is a tumor suppressor and mediates resistance to PD-1 blockade therapy. Proc Natl Acad Sci USA. 2020;117:6640\u201350.","journal-title":"Proc Natl Acad Sci USA"},{"key":"7191_CR24","doi-asserted-by":"publisher","DOI":"10.1080\/2162402X.2017.1408747","volume":"7","author":"S Du","year":"2018","unstructured":"Du S, McCall N, Park K, Guan Q, Fontina P, Ertel A, et al. Blockade of tumor-expressed PD-1 promotes lung cancer growth. Oncoimmunology. 2018;7:e1408747.","journal-title":"Oncoimmunology"},{"key":"7191_CR25","doi-asserted-by":"publisher","first-page":"1196","DOI":"10.1038\/s41416-022-02084-y","volume":"128","author":"Y Wang","year":"2023","unstructured":"Wang Y, Du J, Gao Z, Sun H, Mei M, Wang Y, et al. Evolving landscape of PD-L2: bring new light to checkpoint immunotherapy. Br J Cancer. 2023;128:1196\u2013207.","journal-title":"Br J Cancer"},{"key":"7191_CR26","doi-asserted-by":"publisher","first-page":"943","DOI":"10.1084\/jem.20130790","volume":"211","author":"Y Xiao","year":"2014","unstructured":"Xiao Y, Yu S, Zhu B, Bedoret D, Bu X, Francisco LM, et al. RGMb is a novel binding partner for PD-L2 and its engagement with PD-L2 promotes respiratory tolerance. J Exp Med. 2014;211:943\u201359.","journal-title":"J Exp Med"},{"key":"7191_CR27","first-page":"58","volume":"1865","author":"Y Xia","year":"2016","unstructured":"Xia Y, Jeffrey Medeiros L, Young KH. Signaling pathway and dysregulation of PD1 and its ligands in lymphoid malignancies. Biochim Biophys Acta. 2016;1865:58\u201371.","journal-title":"Biochim Biophys Acta"},{"key":"7191_CR28","doi-asserted-by":"publisher","first-page":"1856","DOI":"10.1056\/NEJMoa1602252","volume":"375","author":"RL Ferris","year":"2016","unstructured":"Ferris RL, Blumenschein G Jr, Fayette J, Guigay J, Colevas AD, Licitra L, et al. Nivolumab for recurrent squamous-cell carcinoma of the head and neck. N Engl J Med. 2016;375:1856\u201367.","journal-title":"N Engl J Med"},{"key":"7191_CR29","doi-asserted-by":"publisher","first-page":"2018","DOI":"10.1056\/NEJMoa1501824","volume":"372","author":"EB Garon","year":"2015","unstructured":"Garon EB, Rizvi NA, Hui R, Leighl N, Balmanoukian AS, Eder JP, et al. Pembrolizumab for the treatment of non-small-cell lung cancer. N Engl J Med. 2015;372:2018\u201328.","journal-title":"N Engl J Med"},{"key":"7191_CR30","doi-asserted-by":"publisher","first-page":"2521","DOI":"10.1056\/NEJMoa1503093","volume":"372","author":"C Robert","year":"2015","unstructured":"Robert C, Schachter J, Long GV, Arance A, Grob JJ, Mortier L, et al. Pembrolizumab versus ipilimumab in advanced melanoma. N Engl J Med. 2015;372:2521\u201332.","journal-title":"N Engl J Med"},{"key":"7191_CR31","doi-asserted-by":"publisher","first-page":"e001698","DOI":"10.1136\/jitc-2020-001698","volume":"9","author":"Z Yin","year":"2021","unstructured":"Yin Z, Yu M, Ma T, Zhang C, Huang S, Karimzadeh MR. Mechanisms underlying low-clinical responses to PD-1\/PD-L1 blocking antibodies in immunotherapy of cancer: a key role of exosomal PD-L1. J Immunother Cancer. 2021;9:e001698","journal-title":"J Immunother Cancer"},{"key":"7191_CR32","doi-asserted-by":"publisher","first-page":"694","DOI":"10.1245\/s10434-015-4903-7","volume":"23","author":"SJ Shin","year":"2016","unstructured":"Shin SJ, Jeon YK, Kim PJ, Cho YM, Koh J, Chung DH, et al. Clinicopathologic analysis of PD-L1 and PD-L2 expression in renal cell carcinoma: association with oncogenic proteins status. Ann Surg Oncol. 2016;23:694\u2013702.","journal-title":"Ann Surg Oncol"},{"key":"7191_CR33","doi-asserted-by":"publisher","first-page":"378","DOI":"10.1038\/nature21386","volume":"543","author":"Cancer Genome Atlas Research N, Albert Einstein College of M, Analytical Biological S, Barretos Cancer H, Baylor College of M, Beckman Research Institute of City of H.","year":"2017","unstructured":"Cancer Genome Atlas Research N, Albert Einstein College of M, Analytical Biological S, Barretos Cancer H, Baylor College of M, Beckman Research Institute of City of H. et al. Integrated genomic and molecular characterization of cervical cancer. Nature. 2017;543:378\u201384.","journal-title":"Nature"},{"key":"7191_CR34","doi-asserted-by":"publisher","DOI":"10.1186\/s40425-019-0703-0","volume":"7","author":"Y Zhang","year":"2019","unstructured":"Zhang Y, Xu J, Hua J, Liu J, Liang C, Meng Q, et al. A PD-L2-based immune marker signature helps to predict survival in resected pancreatic ductal adenocarcinoma. J Immunother Cancer. 2019;7:233.","journal-title":"J Immunother Cancer"},{"key":"7191_CR35","doi-asserted-by":"publisher","first-page":"672","DOI":"10.1016\/S0006-291X(03)01257-9","volume":"307","author":"P Youngnak","year":"2003","unstructured":"Youngnak P, Kozono Y, Kozono H, Iwai H, Otsuki N, Jin H, et al. Differential binding properties of B7-H1 and B7-DC to programmed death-1. Biochemi Biophys Res Commun. 2003;307:672\u20137.","journal-title":"Biochemi Biophys Res Commun"},{"key":"7191_CR36","doi-asserted-by":"publisher","first-page":"377","DOI":"10.1038\/s41586-023-06026-3","volume":"617","author":"JS Park","year":"2023","unstructured":"Park JS, Gazzaniga FS, Wu M, Luthens AK, Gillis J, Zheng W, et al. Targeting PD-L2-RGMb overcomes microbiome-related immunotherapy resistance. Nature. 2023;617:377\u201385.","journal-title":"Nature"},{"key":"7191_CR37","doi-asserted-by":"publisher","first-page":"414","DOI":"10.1016\/j.cell.2019.02.016","volume":"177","author":"M Poggio","year":"2019","unstructured":"Poggio M, Hu T, Pai CC, Chu B, Belair CD, Chang A, et al. Suppression of exosomal PD-L1 Induces systemic anti-tumor immunity and memory. Cell. 2019;177:414\u201327 e13.","journal-title":"Cell"},{"key":"7191_CR38","doi-asserted-by":"publisher","first-page":"382","DOI":"10.1038\/s41586-018-0392-8","volume":"560","author":"G Chen","year":"2018","unstructured":"Chen G, Huang AC, Zhang W, Zhang G, Wu M, Xu W, et al. Exosomal PD-L1 contributes to immunosuppression and is associated with anti-PD-1 response. Nature. 2018;560:382\u20136.","journal-title":"Nature"}],"container-title":["Cell Death &amp; Disease"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41419-024-07191-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41419-024-07191-7","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41419-024-07191-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,11,7]],"date-time":"2024-11-07T08:05:47Z","timestamp":1730966747000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41419-024-07191-7"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,11,7]]},"references-count":38,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2024,11]]}},"alternative-id":["7191"],"URL":"https:\/\/doi.org\/10.1038\/s41419-024-07191-7","relation":{},"ISSN":["2041-4889"],"issn-type":[{"value":"2041-4889","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,11,7]]},"assertion":[{"value":"7 May 2024","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"24 October 2024","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"28 October 2024","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"7 November 2024","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}},{"value":"This study was conducted in compliance with the principles of the Declaration of Helsinki. Informed consent was obtained from all the subjects. Ethics approval for human subjects was provided by the Medical Ethics Committees of ZhongDa Hospital Southeast University (Nanjing, China). Ethics approval for animal work was provided by the Ethics Committee for the Use of Experimental Animals of the Suzhou Institute of Biomedical Engineering and Technology, Chinese Academy of Sciences (Suzhou, Jiangsu, China).","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}}],"article-number":"800"}}