{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T08:55:31Z","timestamp":1790499331219,"version":"4.1.0"},"reference-count":50,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"9","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["JAHA"],"published-print":{"date-parts":[[2019,5,7]]},"abstract":"\n Background<\/jats:title>\n \n CD<\/jats:styled-content>\n 34\n +<\/jats:sup>\n stem\/progenitor cells are involved in vascular homeostasis and in neovascularization of ischemic tissues. The number of circulating\n CD<\/jats:styled-content>\n 34\n +<\/jats:sup>\n stem cells is a predictive biomarker of adverse cardiovascular outcomes in diabetic patients. Here, we provide evidence that hyperglycemia can be \u201cmemorized\u201d by the stem cells through epigenetic changes that contribute to onset and maintenance of their dysfunction in diabetes mellitus.\n <\/jats:p>\n <\/jats:sec>\n \n Methods and Results<\/jats:title>\n \n Cord\u2010blood\u2013derived\n CD<\/jats:styled-content>\n 34\n +<\/jats:sup>\n stem cells exposed to high glucose displayed increased reactive oxygen species production, overexpression of p66\n shc<\/jats:sup>\n gene, and downregulation of antioxidant genes catalase and manganese superoxide dismutase when compared with normoglycemic cells. This altered oxidative state was associated with impaired migration ability toward stromal\u2010cell\u2013derived factor 1 alpha and reduced protein and\n mRNA<\/jats:styled-content>\n expression of the C\u2010X\u2010C chemokine receptor type 4 (\n CXCR<\/jats:styled-content>\n 4) receptor. The methylation analysis by bisulfite Sanger sequencing of the\n CXCR<\/jats:styled-content>\n 4 promoter revealed a significant increase in\n DNA<\/jats:styled-content>\n methylation density in high\u2010glucose\n CD<\/jats:styled-content>\n 34\n +<\/jats:sup>\n stem cells that negatively correlated with\n mRNA<\/jats:styled-content>\n expression (Pearson\n r<\/jats:italic>\n =\u22120.76;\n P<\/jats:italic>\n =0.004). Consistently, we found, by chromatin immunoprecipitation assay, a more transcriptionally inactive chromatin conformation and reduced\n RNA<\/jats:styled-content>\n polymerase\n II<\/jats:styled-content>\n engagement on the\n CXCR<\/jats:styled-content>\n 4 promoter. Notably, alteration of\n CXCR<\/jats:styled-content>\n 4\n DNA<\/jats:styled-content>\n methylation, as well as transcriptional and functional defects, persisted in high\u2010glucose\n CD<\/jats:styled-content>\n 34\n +<\/jats:sup>\n stem cells despite recovery in normoglycemic conditions. Importantly, such an epigenetic modification was thoroughly confirmed in bone marrow\n CD<\/jats:styled-content>\n 34\n +<\/jats:sup>\n stem cells isolated from sternal biopsies of diabetic patients undergoing coronary bypass surgery.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusions<\/jats:title>\n \n CD<\/jats:styled-content>\n 34\n +<\/jats:sup>\n stem cells \u201cmemorize\u201d the hyperglycemic environment in the form of epigenetic modifications that collude to alter\n CXCR<\/jats:styled-content>\n 4 receptor expression and migration.\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1161\/jaha.118.010012","type":"journal-article","created":{"date-parts":[[2019,4,25]],"date-time":"2019-04-25T09:01:10Z","timestamp":1556182870000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":40,"title":["Abnormal DNA Methylation Induced by Hyperglycemia Reduces CXCR4 Gene Expression in CD34\n +<\/sup>\n Stem Cells"],"prefix":"10.1161","volume":"8","author":[{"given":"Vera","family":"Vigorelli","sequence":"first","affiliation":[{"name":"IRCCS Centro Cardiologico Monzino Milan Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jessica","family":"Resta","sequence":"additional","affiliation":[{"name":"IRCCS Centro Cardiologico Monzino Milan Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valentina","family":"Bianchessi","sequence":"additional","affiliation":[{"name":"IRCCS Centro Cardiologico Monzino Milan Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Lauri","sequence":"additional","affiliation":[{"name":"Molecular Biology Unit Axxam SpA Milan Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Beatrice","family":"Bassetti","sequence":"additional","affiliation":[{"name":"IRCCS Centro Cardiologico Monzino Milan Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marco","family":"Agrifoglio","sequence":"additional","affiliation":[{"name":"IRCCS Centro Cardiologico Monzino Milan Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maurizio","family":"Pesce","sequence":"additional","affiliation":[{"name":"IRCCS Centro Cardiologico Monzino Milan Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gianluca","family":"Polvani","sequence":"additional","affiliation":[{"name":"IRCCS Centro Cardiologico Monzino Milan Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giorgia","family":"Bonalumi","sequence":"additional","affiliation":[{"name":"IRCCS Centro Cardiologico Monzino Milan Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Cavallotti","sequence":"additional","affiliation":[{"name":"IRCCS Centro Cardiologico Monzino Milan Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesco","family":"Alamanni","sequence":"additional","affiliation":[{"name":"IRCCS Centro Cardiologico Monzino Milan Italy"},{"name":"Department of Clinical Sciences and Community Health Universit\u00e0 degli Studi di Milano Milan Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefano","family":"Genovese","sequence":"additional","affiliation":[{"name":"IRCCS Centro Cardiologico Monzino Milan Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giulio","family":"Pompilio","sequence":"additional","affiliation":[{"name":"IRCCS Centro Cardiologico Monzino Milan Italy"},{"name":"Department of Clinical Sciences and Community Health Universit\u00e0 degli Studi di Milano Milan Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Cristina","family":"Vinci","sequence":"additional","affiliation":[{"name":"IRCCS Centro Cardiologico Monzino Milan Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-4614-5441-0_17"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2011.07.015"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1093\/eurheartj\/eht149"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.116.308802"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa043814"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1038\/7434"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCINTERVENTIONS.112.968321"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.0000039526.42991.93"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1161\/ATVBAHA.114.303809"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.2337\/dc16-1755"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.2337\/diab.36.7.808"},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa0802743"},{"key":"e_1_3_2_14_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa052187"},{"key":"e_1_3_2_15_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa0808431"},{"key":"e_1_3_2_16_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.115.306424"},{"key":"e_1_3_2_17_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCGENETICS.114.000671"},{"key":"e_1_3_2_18_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.diabres.2014.03.019"},{"key":"e_1_3_2_19_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20081188"},{"key":"e_1_3_2_20_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.biocel.2014.04.014"},{"key":"e_1_3_2_21_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.metabol.2014.05.014"},{"key":"e_1_3_2_22_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajpath.2015.05.003"},{"key":"e_1_3_2_23_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.112.266593"},{"key":"e_1_3_2_24_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0022158"},{"key":"e_1_3_2_25_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ab.2016.12.016"},{"key":"e_1_3_2_26_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.mito.2016.02.004"},{"key":"e_1_3_2_27_2","doi-asserted-by":"publisher","DOI":"10.2337\/db12-1648"},{"key":"e_1_3_2_28_2","doi-asserted-by":"publisher","DOI":"10.1093\/cvr\/cvs132"},{"key":"e_1_3_2_29_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00125-008-0939-6"},{"key":"e_1_3_2_30_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M707451200"},{"key":"e_1_3_2_31_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.thromres.2010.03.002"},{"key":"e_1_3_2_32_2","doi-asserted-by":"publisher","DOI":"10.4161\/cbt.4.1.1378"},{"key":"e_1_3_2_33_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0029461"},{"key":"e_1_3_2_34_2","doi-asserted-by":"publisher","DOI":"10.1634\/stemcells.2008-0377"},{"key":"e_1_3_2_35_2","doi-asserted-by":"publisher","DOI":"10.1038\/embor.2011.110"},{"key":"e_1_3_2_36_2","doi-asserted-by":"publisher","DOI":"10.1101\/gad.276568.115"},{"key":"e_1_3_2_37_2","doi-asserted-by":"publisher","DOI":"10.1001\/jama.299.24.2877"},{"key":"e_1_3_2_38_2","doi-asserted-by":"publisher","DOI":"10.2337\/db08-1666"},{"key":"e_1_3_2_39_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.108.175190"},{"key":"e_1_3_2_40_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0803623105"},{"key":"e_1_3_2_41_2","doi-asserted-by":"publisher","DOI":"10.1186\/s12986-018-0283-x"},{"key":"e_1_3_2_42_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.numecd.2016.04.002"},{"key":"e_1_3_2_43_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.ATV.0000142810.27849.8f"},{"key":"e_1_3_2_44_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.ATV.0000146815.54702.75"},{"key":"e_1_3_2_45_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0968-0004(96)10033-5"},{"key":"e_1_3_2_46_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1069004"},{"key":"e_1_3_2_47_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M106912200"},{"key":"e_1_3_2_48_2","first-page":"5930","article-title":"Multiple actions of the chemokine CXCL12 on epithelial tumor cells in human ovarian cancer","volume":"62","author":"Scotton CJ","year":"2002","unstructured":"Scotton CJ, Wilson JL, Scott K, Stamp G, Wilbanks GD, Fricker S, Bridger G, Balkwill FR. Multiple actions of the chemokine CXCL12 on epithelial tumor cells in human ovarian cancer. Can Res. 2002;62:5930\u20135938.","journal-title":"Can Res"},{"key":"e_1_3_2_49_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.97.10.5237"},{"key":"e_1_3_2_50_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2009.07.011"},{"key":"e_1_3_2_51_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbagrm.2014.02.007"}],"container-title":["Journal of the American Heart Association"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.ahajournals.org\/doi\/full\/10.1161\/JAHA.118.010012","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,5,13]],"date-time":"2024-05-13T11:38:44Z","timestamp":1715600324000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.ahajournals.org\/doi\/10.1161\/JAHA.118.010012"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,5,7]]},"references-count":50,"journal-issue":{"issue":"9","published-print":{"date-parts":[[2019,5,7]]}},"alternative-id":["10.1161\/JAHA.118.010012"],"URL":"https:\/\/doi.org\/10.1161\/jaha.118.010012","relation":{},"ISSN":["2047-9980"],"issn-type":[{"value":"2047-9980","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,5,7]]},"assertion":[{"value":"2018-06-14","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2019-03-14","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2019-04-25","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e010012"}}