{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T11:21:34Z","timestamp":1791372094790,"version":"4.3.1"},"reference-count":31,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2020,2,21]],"date-time":"2020-02-21T00:00:00Z","timestamp":1582243200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2020,2,21]],"date-time":"2020-02-21T00:00:00Z","timestamp":1582243200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100014717","name":"National Outstanding Youth Science Fund Project of National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81900253"],"award-info":[{"award-number":["81900253"]}],"id":[{"id":"10.13039\/100014717","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Stem Cell Res Ther"],"published-print":{"date-parts":[[2020,12]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Human-induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) have shed great light on cardiac regenerative medicine and specifically myocardial repair in heart failure patients. However, the treatment efficacy and the survival of iPSC-CMs in vivo after transplantation have yielded inconsistent results.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objectives<\/jats:title>\n                    <jats:p>The objective of this study was to evaluate the ability of human iPSC-CMs to improve myocardial function in a rat postinfarction heart failure model.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Eight-week-old male Sprague-Dawley rats were randomly selected to receive an intramyocardial injection of 5% albumin solution with or without 1\u2009\u00d7\u200910\n                      <jats:sup>7<\/jats:sup>\n                      human iPSC-CMs 10\u2009days after undergoing left anterior descending (LAD) coronary artery ligation. Cyclosporine A and methylprednisolone were administered before iPSC-CM injection and until the rats were killed to prevent graft rejection. Cardiac function was evaluated by echocardiography. The survival of grafted cardiomyocytes was confirmed by observing the fluorescent cell tracer Vybrant\u2122 CM-DiI or expression of the enhanced green fluorescent protein (eGFP) in transplanted cells, or survival was demonstrated by polymerase chain reaction (PCR)-based detection of human mitochondrial DNA. Sirius red stain was used to evaluate the fibrosis ratio. Hematoxylin-eosin staining was used to observe the formation of teratomas.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Four weeks after intramyocardial injection of iPSC-CMs, animals undergoing iPSC-CM transplantation had lower mortality than the control group. Animals injected with cell-free solution (control group) demonstrated significant left ventricular (LV) functional deterioration, whereas grafting of iPSC-CMs attenuated this remodeling process. In the control group, the ejection fraction deteriorated by 10.11% (from 46.36 to 41.67%), and fractional shortening deteriorated by 9.23% (from 24.37 to 22.12%) by 4\u2009weeks. In the iPSC-CM injection group, the ejection fraction improved by 18.86% (from 44.09 to 52.41%), and fractional shortening improved by 23.69% (from 23.08 to 28.54%). Cell labeling, tracking, and molecular biology techniques indicated that the grafted cardiomyocytes survived in the rat heart 1\u00a0month after iPSC-CM transplantation. Myocardial fibrosis was also attenuated in the iPSC-CM treatment group.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Human iPSC-CM grafts survived in infarcted rat hearts and restored myocardial function 4\u2009weeks after transplantation. Cell replacement therapy also reversed ventricular remodeling, indicating the potential of iPSC-CMs for cardiac repair strategies.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s13287-020-01602-0","type":"journal-article","created":{"date-parts":[[2020,2,21]],"date-time":"2020-02-21T06:02:56Z","timestamp":1582264976000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":74,"title":["Transplantation of human induced pluripotent stem cell-derived cardiomyocytes improves myocardial function and reverses ventricular remodeling in infarcted rat hearts"],"prefix":"10.1186","volume":"11","author":[{"given":"Xumin","family":"Guan","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wanzi","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"He","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qian","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiuyang","family":"Yu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruyi","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yamin","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yunlong","family":"Xia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiaxian","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dongjin","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2020,2,21]]},"reference":[{"issue":"9859","key":"1602_CR1","doi-asserted-by":"crossref","first-page":"2095","DOI":"10.1016\/S0140-6736(12)61728-0","volume":"380","author":"R Lozano","year":"2012","unstructured":"Lozano R, Naghavi M, Foreman K, et al. Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet. 2012;380(9859):2095\u2013128.","journal-title":"Lancet"},{"issue":"11","key":"1602_CR2","doi-asserted-by":"publisher","first-page":"1306","DOI":"10.1002\/ejhf.1594","volume":"21","author":"Nicholas R. Jones","year":"2019","unstructured":"Jones NR, Roalfe AK, Adoki I, et al. Survival of patients with chronic heart failure in the community: a systematic review and meta-analysis. Eur J Heart Fail. 2019;21(11):1306\u20131325.","journal-title":"European Journal of Heart Failure"},{"issue":"7347","key":"1602_CR3","doi-asserted-by":"publisher","first-page":"326","DOI":"10.1038\/nature10147","volume":"473","author":"MA Laflamme","year":"2011","unstructured":"Laflamme MA, Murry CE. Heart regeneration. Nature. 2011;473(7347):326\u201335.","journal-title":"Nature"},{"issue":"1","key":"1602_CR4","first-page":"9","volume":"70","author":"Y Sawa","year":"2017","unstructured":"Sawa Y. Surgical regeneration therapy using myoblast sheets for severe heart failure. Kyobu Geka. 2017;70(1):9\u201313.","journal-title":"Kyobu Geka"},{"issue":"9","key":"1602_CR5","doi-asserted-by":"publisher","first-page":"1777","DOI":"10.1016\/j.jacc.2006.02.002","volume":"47","author":"CE Murry","year":"2006","unstructured":"Murry CE, Reinecke H, Pabon LM. Regeneration gaps: observations on stem cells and cardiac repair. J Am Coll Cardiol. 2006;47(9):1777\u201385.","journal-title":"J Am Coll Cardiol"},{"issue":"1","key":"1602_CR6","doi-asserted-by":"publisher","first-page":"16","DOI":"10.1016\/j.stem.2011.12.013","volume":"10","author":"PW Burridge","year":"2012","unstructured":"Burridge PW, Keller G, Gold JD, et al. Production of de novo cardiomyocytes: human pluripotent stem cell differentiation and direct reprogramming. Cell Stem Cell. 2012;10(1):16\u201328.","journal-title":"Cell Stem Cell"},{"issue":"5","key":"1602_CR7","doi-asserted-by":"publisher","first-page":"861","DOI":"10.1016\/j.cell.2007.11.019","volume":"131","author":"K Takahashi","year":"2007","unstructured":"Takahashi K, Tanabe K, Ohnuki M, et al. Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell. 2007;131(5):861\u201372.","journal-title":"Cell"},{"issue":"5391","key":"1602_CR8","doi-asserted-by":"publisher","first-page":"1145","DOI":"10.1126\/science.282.5391.1145","volume":"282","author":"JA Thomson","year":"1998","unstructured":"Thomson JA, Itskovitz-Eldor J, Shapiro SS, et al. Embryonic stem cell lines derived from human blastocysts. Science. 1998;282(5391):1145\u20137.","journal-title":"Science"},{"issue":"31","key":"1602_CR9","doi-asserted-by":"publisher","first-page":"25929","DOI":"10.1021\/acsami.7b08777","volume":"9","author":"J Wang","year":"2017","unstructured":"Wang J, Cui C, Nan H, et al. Graphene sheet-induced global maturation of cardiomyocytes derived from human induced pluripotent stem cells. ACS Appl Mater Interfaces. 2017;9(31):25929\u201340.","journal-title":"ACS Appl Mater Interfaces"},{"issue":"4","key":"1602_CR10","doi-asserted-by":"publisher","first-page":"3679","DOI":"10.1021\/acsami.8b17090","volume":"11","author":"C Cui","year":"2019","unstructured":"Cui C, Wang J, Qian D, et al. Binary colloidal crystals drive spheroid formation and accelerate maturation of human-induced pluripotent stem cell-derived cardiomyocytes. ACS Appl Mater Interfaces. 2019;11(4):3679\u201389.","journal-title":"ACS Appl Mater Interfaces"},{"issue":"35","key":"1602_CR11","doi-asserted-by":"publisher","first-page":"8878","DOI":"10.1016\/j.biomaterials.2013.07.039","volume":"34","author":"J Wang","year":"2013","unstructured":"Wang J, Chen A, Lieu DK, et al. Effect of engineered anisotropy on the susceptibility of human pluripotent stem cell-derived ventricular cardiomyocytes to arrhythmias. Biomaterials. 2013;34(35):8878\u201386.","journal-title":"Biomaterials"},{"issue":"48","key":"1602_CR12","doi-asserted-by":"publisher","first-page":"5785","DOI":"10.1002\/adma.201103463","volume":"23","author":"A Chen","year":"2011","unstructured":"Chen A, Lieu DK, Freschauf L, et al. Shrink-film configurable multiscale wrinkles for functional alignment of human embryonic stem cells and their cardiac derivatives [J]. Adv Mater. 2011;23(48):5785\u201391.","journal-title":"Adv Mater"},{"key":"1602_CR13","first-page":"e53447","volume":"109","author":"TJ Cashman","year":"2016","unstructured":"Cashman TJ, Josowitz R, Gelb BD, et al. Construction of defined human engineered cardiac tissues to study mechanisms of cardiac cell therapy. J Vis Exp. 2016;109:e53447.","journal-title":"J Vis Exp"},{"issue":"3","key":"1602_CR14","doi-asserted-by":"publisher","first-page":"407","DOI":"10.1172\/JCI200112131","volume":"108","author":"I Kehat","year":"2001","unstructured":"Kehat I, Kenyagin-Karsenti D, Snir M, et al. Human embryonic stem cells can differentiate into myocytes with structural and functional properties of cardiomyocytes. J Clin Invest. 2001;108(3):407\u201314.","journal-title":"J Clin Invest"},{"issue":"7504","key":"1602_CR15","doi-asserted-by":"publisher","first-page":"273","DOI":"10.1038\/nature13233","volume":"510","author":"JJ Chong","year":"2014","unstructured":"Chong JJ, Yang X, Don CW, et al. Human embryonic-stem-cell-derived cardiomyocytes regenerate non-human primate hearts. Nature. 2014;510(7504):273\u20137.","journal-title":"Nature"},{"issue":"1","key":"1602_CR16","doi-asserted-by":"publisher","first-page":"127","DOI":"10.1016\/j.stem.2012.09.013","volume":"12","author":"S Tohyama","year":"2013","unstructured":"Tohyama S, Hattori F, Sano M, et al. Distinct metabolic flow enables large-scale purification of mouse and human pluripotent stem cell-derived cardiomyocytes. Cell Stem Cell. 2013;12(1):127\u201337.","journal-title":"Cell Stem Cell"},{"issue":"8","key":"1602_CR17","doi-asserted-by":"publisher","first-page":"855","DOI":"10.1038\/nmeth.2999","volume":"11","author":"PW Burridge","year":"2014","unstructured":"Burridge PW, Matsa E, Shukla P, et al. Chemically defined generation of human cardiomyocytes. Nat Methods. 2014;11(8):855\u201360.","journal-title":"Nat Methods"},{"issue":"19","key":"1602_CR18","doi-asserted-by":"publisher","first-page":"1884","DOI":"10.1016\/j.jacc.2007.07.054","volume":"50","author":"O Caspi","year":"2007","unstructured":"Caspi O, Huber I, Kehat I, et al. Transplantation of human embryonic stem cell-derived cardiomyocytes improves myocardial performance in infarcted rat hearts. J Am Coll Cardiol. 2007;50(19):1884\u201393.","journal-title":"J Am Coll Cardiol"},{"issue":"7","key":"1602_CR19","doi-asserted-by":"publisher","first-page":"597","DOI":"10.1038\/nbt.4162","volume":"36","author":"YW Liu","year":"2018","unstructured":"Liu YW, Chen B, Yang X, et al. Human embryonic stem cell-derived cardiomyocytes restore function in infarcted hearts of non-human primates. Nat Biotechnol. 2018;36(7):597\u2013605.","journal-title":"Nat Biotechnol"},{"issue":"undefined","key":"1602_CR20","doi-asserted-by":"publisher","first-page":"277","DOI":"10.1146\/annurev-bioeng-071813-105108","volume":"16","author":"KK Hirschi","year":"2014","unstructured":"Hirschi KK, Li S, Roy K. Induced pluripotent stem cells for regenerative medicine. Annu Rev Biomed Eng. 2014;16(undefined):277\u201394.","journal-title":"Annu Rev Biomed Eng"},{"issue":"7625","key":"1602_CR21","doi-asserted-by":"publisher","first-page":"388","DOI":"10.1038\/nature19815","volume":"538","author":"Y Shiba","year":"2016","unstructured":"Shiba Y, Gomibuchi T, Seto T, et al. Allogeneic transplantation of iPS cell-derived cardiomyocytes regenerates primate hearts. Nature. 2016;538(7625):388\u201391.","journal-title":"Nature"},{"issue":"5","key":"1602_CR22","doi-asserted-by":"publisher","first-page":"1415","DOI":"10.1016\/j.stemcr.2017.09.003","volume":"9","author":"A Chow","year":"2017","unstructured":"Chow A, Stuckey DJ, Kidher E, et al. Human induced pluripotent stem cell-derived cardiomyocyte encapsulating bioactive hydrogels improve rat heart function post myocardial infarction. Stem Cell Rep. 2017;9(5):1415\u201322.","journal-title":"Stem Cell Rep"},{"issue":"6","key":"1602_CR23","doi-asserted-by":"publisher","first-page":"977","DOI":"10.1089\/scd.2011.0075","volume":"21","author":"L Carpenter","year":"2012","unstructured":"Carpenter L, Carr C, Yang CT, et al. Efficient differentiation of human induced pluripotent stem cells generates cardiac cells that provide protection following myocardial infarction in the rat. Stem Cells Dev. 2012;21(6):977\u201386.","journal-title":"Stem Cells Dev"},{"issue":"2","key":"1602_CR24","doi-asserted-by":"publisher","first-page":"422","DOI":"10.1016\/j.stemcr.2018.01.002","volume":"10","author":"X Zhao","year":"2018","unstructured":"Zhao X, Chen H, Xiao D, et al. Comparison of non-human primate versus human induced pluripotent stem cell-derived cardiomyocytes for treatment of myocardial infarction. Stem Cell Rep. 2018;10(2):422\u201335.","journal-title":"Stem Cell Rep"},{"issue":"11","key":"1602_CR25","doi-asserted-by":"publisher","first-page":"1395","DOI":"10.1161\/01.CIR.0000085658.98621.49","volume":"108","author":"BI Jugdutt","year":"2003","unstructured":"Jugdutt BI. Ventricular remodeling after infarction and the extracellular collagen matrix: when is enough enough? Circulation. 2003;108(11):1395\u2013403.","journal-title":"Circulation"},{"issue":"4","key":"1602_CR26","doi-asserted-by":"publisher","first-page":"1161","DOI":"10.1161\/01.CIR.81.4.1161","volume":"81","author":"MA Pfeffer","year":"1990","unstructured":"Pfeffer MA, Braunwald E. Ventricular remodeling after myocardial infarction. Experimental observations and clinical implications. Circulation. 1990;81(4):1161\u201372.","journal-title":"Circulation"},{"issue":"7","key":"1602_CR27","doi-asserted-by":"publisher","first-page":"1005","DOI":"10.1161\/CIRCULATIONAHA.105.588954","volume":"113","author":"F Cao","year":"2006","unstructured":"Cao F, Lin S, Xie X, et al. In vivo visualization of embryonic stem cell survival, proliferation, and migration after cardiac delivery. Circulation. 2006;113(7):1005\u201314.","journal-title":"Circulation"},{"issue":"6","key":"1602_CR28","doi-asserted-by":"publisher","first-page":"e22","DOI":"10.1161\/CIRCRESAHA.117.310803","volume":"121","author":"A Tachibana","year":"2017","unstructured":"Tachibana A, Santoso MR, Mahmoudi M, et al. Paracrine effects of the pluripotent stem cell-derived cardiac myocytes salvage the injured myocardium. Circ Res. 2017;121(6):e22\u201336.","journal-title":"Circ Res"},{"issue":"14","key":"1602_CR29","doi-asserted-by":"publisher","first-page":"1424","DOI":"10.1016\/j.jacc.2015.01.042","volume":"65","author":"A Stempien-Otero","year":"2015","unstructured":"Stempien-Otero A, Helterline D, Plummer T, et al. Mechanisms of bone marrow-derived cell therapy in ischemic cardiomyopathy with left ventricular assist device bridge to transplant. J Am Coll Cardiol. 2015;65(14):1424\u201334.","journal-title":"J Am Coll Cardiol"},{"issue":"9","key":"1602_CR30","doi-asserted-by":"publisher","first-page":"1015","DOI":"10.1038\/nbt1327","volume":"25","author":"MA Laflamme","year":"2007","unstructured":"Laflamme MA, Chen KY, Naumova AV, et al. Cardiomyocytes derived from human embryonic stem cells in pro-survival factors enhance function of infarcted rat hearts. Nat Biotechnol. 2007;25(9):1015\u201324.","journal-title":"Nat Biotechnol"},{"issue":"9 Suppl","key":"1602_CR31","first-page":"I150","volume":"112","author":"D Hou","year":"2005","unstructured":"Hou D, Youssef EA, Brinton TJ, et al. Radiolabeled cell distribution after intramyocardial, intracoronary, and interstitial retrograde coronary venous delivery: implications for current clinical trials. Circulation. 2005;112(9 Suppl):I150\u20136.","journal-title":"Circulation"}],"updated-by":[{"DOI":"10.1186\/s13287-020-01673-z","type":"correction","label":"Correction","source":"publisher","updated":{"date-parts":[[2020,5,27]],"date-time":"2020-05-27T00:00:00Z","timestamp":1590537600000}}],"container-title":["Stem Cell Research &amp; Therapy"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/link.springer.com\/content\/pdf\/10.1186\/s13287-020-01602-0.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/link.springer.com\/article\/10.1186\/s13287-020-01602-0\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/link.springer.com\/content\/pdf\/10.1186\/s13287-020-01602-0.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,2,20]],"date-time":"2021-02-20T20:06:38Z","timestamp":1613851598000},"score":1,"resource":{"primary":{"URL":"https:\/\/stemcellres.biomedcentral.com\/articles\/10.1186\/s13287-020-01602-0"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,2,21]]},"references-count":31,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2020,12]]}},"alternative-id":["1602"],"URL":"https:\/\/doi.org\/10.1186\/s13287-020-01602-0","relation":{},"ISSN":["1757-6512"],"issn-type":[{"value":"1757-6512","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,2,21]]},"assertion":[{"value":"11 November 2019","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"21 January 2020","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"12 February 2020","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"21 February 2020","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"27 May 2020","order":5,"name":"change_date","label":"Change Date","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"Correction","order":6,"name":"change_type","label":"Change Type","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The original article omits an affiliation for authors, He Zhang and Dongjin Wang. The omitted affiliation can be viewed in this Correction article.","order":7,"name":"change_details","label":"Change Details","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"All animal experiments were approved by the Institutional Animal Care and Use Committee (IACUC-1805001) of Nanjing Medical University and in accordance with the Regulations for the Administration of Affairs Concerning Experimental Animals.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare that they have no competing interests","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}},{"value":"Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Publisher\u2019s Note"}}],"article-number":"73"}}