{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T17:57:32Z","timestamp":1790704652300,"version":"4.1.0"},"reference-count":45,"publisher":"Oxford University Press (OUP)","issue":"12","license":[{"start":{"date-parts":[[2015,11,12]],"date-time":"2015-11-12T00:00:00Z","timestamp":1447286400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81120108003"],"award-info":[{"award-number":["81120108003"]}],"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":["81330007"],"award-info":[{"award-number":["81330007"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Guangdong Science and Technology Program of International Cooperation Project","award":["2014A050503047"],"award-info":[{"award-number":["2014A050503047"]}]},{"name":"Zhujiang Science and Technology New Star of Guangzhou","award":["2011J2200049"],"award-info":[{"award-number":["2011J2200049"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2015,12,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title\/>\n                    <jats:p>The reprogramming of fibroblasts to induced pluripotent stem cells raises the possibility that somatic cells could be directly reprogrammed to cardiac progenitor cells (CPCs). The present study aimed to assess highly efficient protein-based approaches to reduce or eliminate the genetic manipulations to generate CPCs for cardiac regeneration therapy. A combination of QQ-reagent-modified Gata4, Hand2, Mef2c, and Tbx5 and three cytokines rapidly and efficiently reprogrammed human dermal fibroblasts (HDFs) into CPCs. This reprogramming process enriched trimethylated histone H3 lysine 4, monoacetylated histone H3 lysine 9, and Baf60c at the Nkx2.5 cardiac enhancer region by the chromatin immunoprecipitation quantitative polymerase chain reaction assay. Protein-induced CPCs transplanted into rat hearts after myocardial infarction improved cardiac function, and this was related to differentiation into cardiomyocyte-like cells. These findings demonstrate that the highly efficient protein-transduction method can directly reprogram HDFs into CPCs. This protein reprogramming strategy lays the foundation for future refinements both in vitro and in vivo and might provide a source of CPCs for regenerative approaches.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Significance<\/jats:title>\n                    <jats:p>The findings from the present study have demonstrated an efficient protein-transduction method of directly reprogramming fibroblasts into cardiac progenitor cells. These results have great potential in cell-based therapy for cardiovascular diseases.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.5966\/sctm.2015-0136","type":"journal-article","created":{"date-parts":[[2015,11,12]],"date-time":"2015-11-12T20:58:37Z","timestamp":1447361917000},"page":"1415-1424","source":"Crossref","is-referenced-by-count":41,"title":["Generation of Functional Human Cardiac Progenitor Cells by High-Efficiency Protein Transduction"],"prefix":"10.1093","volume":"4","author":[{"given":"Xiao-Hong","family":"Li","sequence":"first","affiliation":[{"name":"Guangdong Cardiovascular Institute of Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, People's Republic of China"},{"name":"Biochemistry and Molecular Biology Department, Wayne State University School of Medicine, Detroit, Michigan, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qianqian","family":"Li","sequence":"additional","affiliation":[{"name":"Biochemistry and Molecular Biology Department, Wayne State University School of Medicine, Detroit, Michigan, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lin","family":"Jiang","sequence":"additional","affiliation":[{"name":"Guangdong Cardiovascular Institute of Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chunyu","family":"Deng","sequence":"additional","affiliation":[{"name":"Guangdong Cardiovascular Institute of Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zaiyi","family":"Liu","sequence":"additional","affiliation":[{"name":"Guangdong Cardiovascular Institute of Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yongheng","family":"Fu","sequence":"additional","affiliation":[{"name":"Guangdong Cardiovascular Institute of Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mengzhen","family":"Zhang","sequence":"additional","affiliation":[{"name":"Guangdong Cardiovascular Institute of Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Honghong","family":"Tan","sequence":"additional","affiliation":[{"name":"Guangdong Cardiovascular Institute of Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuliang","family":"Feng","sequence":"additional","affiliation":[{"name":"Guangdong Cardiovascular Institute of Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhixin","family":"Shan","sequence":"additional","affiliation":[{"name":"Guangdong Cardiovascular Institute of Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianjun","family":"Wang","sequence":"additional","affiliation":[{"name":"Biochemistry and Molecular Biology Department, Wayne State University School of Medicine, Detroit, Michigan, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xi-Yong","family":"Yu","sequence":"additional","affiliation":[{"name":"Guangdong Cardiovascular Institute of Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, People's Republic of China"},{"name":"School of Pharmaceutical Sciences, Guangzhou Medical University, Guangzhou, People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2015,11,12]]},"reference":[{"key":"2021122704434978100_R1","doi-asserted-by":"crossref","first-page":"1513","DOI":"10.1161\/CIRCULATIONAHA.109.868885","article-title":"Cardiomyocyte differentiation of human induced pluripotent stem cells","volume":"120","author":"Zwi","year":"2009","journal-title":"Circulation"},{"key":"2021122704434978100_R2","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1016\/j.yjmcc.2006.07.002","article-title":"Bone marrow mesenchymal stem cells differentiate into functional cardiac phenotypes by cardiac microenvironment","volume":"42","author":"Li","year":"2007","journal-title":"J Mol Cell Cardiol"},{"key":"2021122704434978100_R3","doi-asserted-by":"crossref","first-page":"462","DOI":"10.1002\/stem.1571","article-title":"Heat shock improves Sca-1+ stem cell survival and directs ischemic cardiomyocytes toward a prosurvival phenotype via exosomal transfer: a critical role for HSF1\/miR-34a\/HSP70 pathway","volume":"32","author":"Feng","year":"2014","journal-title":"Stem Cells"},{"key":"2021122704434978100_R4","doi-asserted-by":"crossref","first-page":"1847","DOI":"10.1016\/S0140-6736(11)61590-0","article-title":"Cardiac stem cells in patients with ischaemic cardiomyopathy (SCIPIO): Initial results of a randomised phase 1 trial","volume":"378","author":"Bolli","year":"2011","journal-title":"Lancet"},{"key":"2021122704434978100_R5","doi-asserted-by":"crossref","first-page":"895","DOI":"10.1016\/S0140-6736(12)60195-0","article-title":"Intracoronary cardiosphere-derived cells for heart regeneration after myocardial infarction (CADUCEUS): A prospective, randomised phase 1 trial","volume":"379","author":"Makkar","year":"2012","journal-title":"Lancet"},{"key":"2021122704434978100_R6","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1016\/j.jacc.2013.08.724","article-title":"Intracoronary cardiosphere-derived cells after myocardial infarction: Evidence of therapeutic regeneration in the final 1-year results of the CADUCEUS trial (CArdiosphere-Derived aUtologous stem CElls to reverse ventricUlar dySfunction)","volume":"63","author":"Malliaras","year":"2014","journal-title":"J Am Coll Cardiol"},{"key":"2021122704434978100_R7","doi-asserted-by":"crossref","first-page":"326","DOI":"10.1038\/nature10147","article-title":"Heart regeneration","volume":"473","author":"Laflamme","year":"2011","journal-title":"Nature"},{"key":"2021122704434978100_R8","doi-asserted-by":"crossref","first-page":"689","DOI":"10.1016\/j.stem.2013.05.008","article-title":"Cardiac stem cell therapy and the promise of heart regeneration","volume":"12","author":"Garbern","year":"2013","journal-title":"Cell Stem Cell"},{"key":"2021122704434978100_R9","doi-asserted-by":"crossref","first-page":"663","DOI":"10.1016\/j.cell.2006.07.024","article-title":"Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors","volume":"126","author":"Takahashi","year":"2006","journal-title":"Cell"},{"key":"2021122704434978100_R10","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1038\/ncb2164","article-title":"Conversion of mouse fibroblasts into cardiomyocytes using a direct reprogramming strategy","volume":"13","author":"Efe","year":"2011","journal-title":"Nat Cell Biol"},{"key":"2021122704434978100_R11","doi-asserted-by":"crossref","first-page":"951","DOI":"10.1016\/j.celrep.2014.01.038","article-title":"Small molecules enable cardiac reprogramming of mouse fibroblasts with a single factor, Oct4","volume":"6","author":"Wang","year":"2014","journal-title":"Cell Rep"},{"key":"2021122704434978100_R12","doi-asserted-by":"crossref","first-page":"708","DOI":"10.1038\/nature08039","article-title":"Directed transdifferentiation of mouse mesoderm to heart tissue by defined factors","volume":"459","author":"Takeuchi","year":"2009","journal-title":"Nature"},{"key":"2021122704434978100_R13","doi-asserted-by":"crossref","first-page":"375","DOI":"10.1016\/j.cell.2010.07.002","article-title":"Direct reprogramming of fibroblasts into functional cardiomyocytes by defined factors","volume":"142","author":"Ieda","year":"2010","journal-title":"Cell"},{"key":"2021122704434978100_R14","doi-asserted-by":"crossref","first-page":"593","DOI":"10.1038\/nature11044","article-title":"In vivo reprogramming of murine cardiac fibroblasts into induced cardiomyocytes","volume":"485","author":"Qian","year":"2012","journal-title":"Nature"},{"key":"2021122704434978100_R15","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1161\/CIRCRESAHA.112.270264","article-title":"Inefficient reprogramming of fibroblasts into cardiomyocytes using Gata4, Mef2c, and Tbx5","volume":"111","author":"Chen","year":"2012","journal-title":"Circ Res"},{"key":"2021122704434978100_R16","doi-asserted-by":"crossref","first-page":"599","DOI":"10.1038\/nature11139","article-title":"Heart repair by reprogramming non-myocytes with cardiac transcription factors","volume":"485","author":"Song","year":"2012","journal-title":"Nature"},{"key":"2021122704434978100_R17","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1016\/j.stemcr.2013.07.005","article-title":"Direct reprogramming of human fibroblasts toward a cardiomyocyte-like state","volume":"1","author":"Fu","year":"2013","journal-title":"Stem Cell Rep"},{"key":"2021122704434978100_R18","doi-asserted-by":"crossref","first-page":"323","DOI":"10.1016\/j.yjmcc.2012.04.010","article-title":"A new approach to transcription factor screening for reprogramming of fibroblasts to cardiomyocyte-like cells","volume":"53","author":"Protze","year":"2012","journal-title":"J Mol Cell Cardiol"},{"key":"2021122704434978100_R19","doi-asserted-by":"crossref","first-page":"5588","DOI":"10.1073\/pnas.1301019110","article-title":"Reprogramming of human fibroblasts toward a cardiac fate","volume":"110","author":"Nam","year":"2013","journal-title":"Proc Natl Acad Sci USA"},{"key":"2021122704434978100_R20","doi-asserted-by":"crossref","first-page":"1465","DOI":"10.1161\/CIRCRESAHA.112.269035","article-title":"MicroRNA-mediated in vitro and in vivo direct reprogramming of cardiac fibroblasts to cardiomyocytes","volume":"110","author":"Jayawardena","year":"2012","journal-title":"Circ Res"},{"key":"2021122704434978100_R21","doi-asserted-by":"crossref","first-page":"1565","DOI":"10.15252\/embj.201387605","article-title":"MiR-133 promotes cardiac reprogramming by directly repressing Snai1 and silencing fibroblast signatures","volume":"33","author":"Muraoka","year":"2014","journal-title":"EMBO J"},{"key":"2021122704434978100_R22","doi-asserted-by":"crossref","first-page":"386","DOI":"10.1182\/blood-2010-02-269589","article-title":"Induction of pluripotent stem cells from adult somatic cells by protein-based reprogramming without genetic manipulation","volume":"116","author":"Cho","year":"2010","journal-title":"Blood"},{"key":"2021122704434978100_R23","doi-asserted-by":"crossref","first-page":"4330","DOI":"10.1242\/dev.086116","article-title":"Epigenetic reprogramming in somatic cells induced by extract from germinal vesicle stage pig oocytes","volume":"139","author":"Bui","year":"2012","journal-title":"Development"},{"key":"2021122704434978100_R24","doi-asserted-by":"crossref","first-page":"381","DOI":"10.1016\/j.stem.2009.04.005","article-title":"Generation of induced pluripotent stem cells using recombinant proteins","volume":"4","author":"Zhou","year":"2009","journal-title":"Cell Stem Cell"},{"key":"2021122704434978100_R25","doi-asserted-by":"crossref","first-page":"1000","DOI":"10.1002\/mrd.22263","article-title":"Activation of pluripotency genes by a nanotube-mediated protein delivery system","volume":"80","author":"Cho","year":"2013","journal-title":"Mol Reprod Dev"},{"key":"2021122704434978100_R26","doi-asserted-by":"crossref","first-page":"13016","DOI":"10.1073\/pnas.1120299109","article-title":"Transcription factors ETS2 and MESP1 transdifferentiate human dermal fibroblasts into cardiac progenitors","volume":"109","author":"Islas","year":"2012","journal-title":"Proc Natl Acad Sci USA"},{"key":"2021122704434978100_R27","doi-asserted-by":"crossref","first-page":"287","DOI":"10.1016\/S0091-679X(08)00814-5","article-title":"Real time investigation of protein folding, structure, and dynamics in living cells","volume":"90","author":"Li","year":"2008","journal-title":"Methods Cell Biol"},{"key":"2021122704434978100_R28","doi-asserted-by":"crossref","first-page":"723","DOI":"10.1016\/j.devcel.2006.10.002","article-title":"Multipotent flk-1+ cardiovascular progenitor cells give rise to the cardiomyocyte, endothelial, and vascular smooth muscle lineages","volume":"11","author":"Kattman","year":"2006","journal-title":"Dev Cell"},{"key":"2021122704434978100_R29","doi-asserted-by":"crossref","first-page":"297","DOI":"10.1016\/j.ydbio.2007.08.004","article-title":"The amphibian second heart field: Xenopus islet-1 is required for cardiovascular development","volume":"311","author":"Brade","year":"2007","journal-title":"Dev Biol"},{"key":"2021122704434978100_R30","doi-asserted-by":"crossref","first-page":"537","DOI":"10.1016\/j.cell.2008.02.002","article-title":"Origins and fates of cardiovascular progenitor cells","volume":"132","author":"Wu","year":"2008","journal-title":"Cell"},{"key":"2021122704434978100_R31","doi-asserted-by":"crossref","first-page":"5357","DOI":"10.1242\/dev.065565","article-title":"Molecular basis for Flk1 expression in hemato-cardiovascular progenitors in the mouse","volume":"138","author":"Ishitobi","year":"2011","journal-title":"Development"},{"key":"2021122704434978100_R32","doi-asserted-by":"crossref","first-page":"393","DOI":"10.1083\/jcb.130.2.393","article-title":"Identification and characterization of a fibroblast marker: FSP1","volume":"130","author":"Strutz","year":"1995","journal-title":"J Cell Biol"},{"key":"2021122704434978100_R33","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1038\/nchembio.137","article-title":"Small molecule-mediated disruption of Wnt-dependent signaling in tissue regeneration and cancer","volume":"5","author":"Chen","year":"2009","journal-title":"Nat Chem Biol"},{"key":"2021122704434978100_R34","doi-asserted-by":"crossref","first-page":"360","DOI":"10.1161\/CIRCRESAHA.111.249540","article-title":"Small-molecule inhibitors of the Wnt pathway potently promote cardiomyocytes from human embryonic stem cell-derived mesoderm","volume":"109","author":"Willems","year":"2011","journal-title":"Circ Res"},{"key":"2021122704434978100_R35","doi-asserted-by":"crossref","first-page":"1513","DOI":"10.1089\/scd.2011.0254","article-title":"Primitive cardiac cells from human embryonic stem cells","volume":"21","author":"Hudson","year":"2012","journal-title":"Stem Cells Dev"},{"key":"2021122704434978100_R36","doi-asserted-by":"crossref","first-page":"206","DOI":"10.1016\/j.cell.2012.07.035","article-title":"Dynamic and coordinated epigenetic regulation of developmental transitions in the cardiac lineage","volume":"151","author":"Wamstad","year":"2012","journal-title":"Cell"},{"key":"2021122704434978100_R37","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1242\/dev.126.1.75","article-title":"Control of early cardiac-specific transcription of Nkx2-5 by a GATA-dependent enhancer","volume":"126","author":"Lien","year":"1999","journal-title":"Development"},{"key":"2021122704434978100_R38","doi-asserted-by":"crossref","first-page":"839","DOI":"10.1242\/dev.126.4.839","article-title":"Identification of upstream regulatory regions in the heart-expressed homeobox gene Nkx2-5","volume":"126","author":"Reecy","year":"1999","journal-title":"Development"},{"key":"2021122704434978100_R39","doi-asserted-by":"crossref","first-page":"335","DOI":"10.1042\/BC20080108","article-title":"NFAT directly regulates Nkx2-5 transcription during cardiac cell differentiation","volume":"101","author":"Chen","year":"2009","journal-title":"Biol Cell"},{"key":"2021122704434978100_R40","doi-asserted-by":"crossref","first-page":"e1001313","DOI":"10.1371\/journal.pgen.1001313","article-title":"The cardiac transcription network modulated by Gata4, Mef2a, Nkx2.5, Srf, histone modifications, and microRNAs","volume":"7","author":"Schlesinger","year":"2011","journal-title":"PLoS Genet"},{"key":"2021122704434978100_R41","doi-asserted-by":"crossref","first-page":"200","DOI":"10.1016\/j.cell.2009.01.009","article-title":"Understanding the words of chromatin regulation","volume":"136","author":"Wu","year":"2009","journal-title":"Cell"},{"key":"2021122704434978100_R42","doi-asserted-by":"crossref","first-page":"1147","DOI":"10.1161\/CIRCRESAHA.112.271148","article-title":"Induction of cardiomyocyte-like cells in infarct hearts by gene transfer of Gata4, Mef2c, and Tbx5","volume":"111","author":"Inagawa","year":"2012","journal-title":"Circ Res"},{"key":"2021122704434978100_R43","doi-asserted-by":"crossref","first-page":"1922","DOI":"10.1126\/science.1132292","article-title":"Gene regulatory networks in the evolution and development of the heart","volume":"313","author":"Olson","year":"2006","journal-title":"Science"},{"key":"2021122704434978100_R44","doi-asserted-by":"crossref","first-page":"1037","DOI":"10.1016\/j.cell.2006.09.003","article-title":"Making or breaking the heart: From lineage determination to morphogenesis","volume":"126","author":"Srivastava","year":"2006","journal-title":"Cell"},{"key":"2021122704434978100_R45","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1038\/nature03071","article-title":"Baf60c is essential for function of BAF chromatin remodelling complexes in heart development","volume":"432","author":"Lickert","year":"2004","journal-title":"Nature"}],"container-title":["Stem Cells Translational Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.5966%2Fsctm.2015-0136","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.5966%2Fsctm.2015-0136","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/academic.oup.com\/stcltm\/article-pdf\/4\/12\/1415\/41865194\/stcltm_4_12_1415.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/stcltm\/article-pdf\/4\/12\/1415\/41865194\/stcltm_4_12_1415.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,1,18]],"date-time":"2022-01-18T21:50:02Z","timestamp":1642542602000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/stcltm\/article\/4\/12\/1415-1424\/6387864"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2015,11,12]]},"references-count":45,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2015,11,12]]},"published-print":{"date-parts":[[2015,12,1]]}},"URL":"https:\/\/doi.org\/10.5966\/sctm.2015-0136","relation":{},"ISSN":["2157-6564","2157-6580"],"issn-type":[{"value":"2157-6564","type":"print"},{"value":"2157-6580","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2015,12,1]]},"published":{"date-parts":[[2015,11,12]]}}}