{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T18:32:53Z","timestamp":1790188373229,"version":"4.1.0"},"reference-count":30,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2017,1,12]],"date-time":"2017-01-12T00:00:00Z","timestamp":1484179200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2017,1,12]],"date-time":"2017-01-12T00:00:00Z","timestamp":1484179200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Cell Death Dis"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Poor cell survival and limited functional benefits have restricted mesenchymal stem cell (MSC) efficacy for treating myocardial infarction (MI), suggesting that a better understanding of stem cell biology is needed. The transcription factor HIF-2<jats:italic>\u03b1<\/jats:italic> is an essential regulator of the transcriptional response to hypoxia, which can interact with embryonic stem cells (ESCs) transcription factor Oct4 and modulate its signaling. Here, we obtained very small embryonic-like mesenchymal stem cells (vselMSCs) from MI patients, which possessed the very small embryonic-like stem cells\u2019 (VSELs) morphology as well as ESCs\u2019 pluripotency. Using microarray analysis, we compared HIF-2<jats:italic>\u03b1<\/jats:italic>-regulated gene profiles in vselMSCs with ESC profiles and determined that HIF-2<jats:italic>\u03b1<\/jats:italic> coexpressed Oct4 in vselMSCs similarly to ESCs. However, this coexpression was absent in unpurified MSCs (uMSCs). Under hypoxic condition, vselMSCs exhibited stronger survival, proliferation and differentiation than uMSCs. Transplantation of vselMSCs caused greater improvement in cardiac function and heart remodeling in the infarcted rats. We further demonstrated that HIF-2<jats:italic>\u03b1<\/jats:italic> and Oct4 jointly regulate their relative downstream gene expressions, including Bcl2 and Survivin; the important pluripotent markers Nanog, Klf4, and Sox2; and Ang-1, bFGF, and VEGF, promoting angiogenesis and engraftment. Importantly, these effects were generally magnified by upregulation of HIF-2<jats:italic>\u03b1<\/jats:italic> and Oct4 induced by HIF-2<jats:italic>\u03b1<\/jats:italic> or Oct4 overexpression, and the greatest improvements were elicited after co-overexpressing HIF-2<jats:italic>\u03b1<\/jats:italic> and Oct4; overexpressing one transcription factor while silencing the other canceled this increase, and HIF-2<jats:italic>\u03b1<\/jats:italic> or Oct4 silencing abolished these effects. Together, these findings demonstrated that HIF-2<jats:italic>\u03b1<\/jats:italic> in vselMSCs cooperated with Oct4 in survival and function. The identification of the cooperation between HIF-2<jats:italic>\u03b1<\/jats:italic> and Oct4 will lead to deeper characterization of the downstream targets of this interaction in vselMSCs and will have novel pathophysiological implications for the repair of infarcted myocardium.<\/jats:p>","DOI":"10.1038\/cddis.2016.480","type":"journal-article","created":{"date-parts":[[2017,1,12]],"date-time":"2017-01-12T13:47:21Z","timestamp":1484228841000},"page":"e2548-e2548","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":38,"title":["HIF-2\u03b1 and Oct4 have synergistic effects on survival and myocardial repair of very small embryonic-like mesenchymal stem cells in infarcted hearts"],"prefix":"10.1038","volume":"8","author":[{"given":"Shaoheng","family":"Zhang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lan","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiahong","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nannan","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jian","family":"Yan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Pan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2017,1,12]]},"reference":[{"key":"BFcddis2016480_CR1","doi-asserted-by":"publisher","first-page":"576","DOI":"10.1161\/CIRCRESAHA.115.306332","volume":"117","author":"EC Perin","year":"2015","unstructured":"Perin EC, Borow KM, Silva GV, DeMaria AN, Marroquin OC, Huang PP et al. A phase II dose-escalation study of allogeneic mesenchymal precursor cells in patients with ischemic or nonischemic heart failure. Circ Res 2015; 117: 576\u2013584.","journal-title":"Circ Res"},{"key":"BFcddis2016480_CR2","first-page":"26","volume":"6","author":"P Dixit","year":"2015","unstructured":"Dixit P, Katare R . Challenges in identifying the best source of\u2002stem\u2002cells\u2002for cardiac regeneration therapy. Stem\u2002Cell\u2002Res Ther 2015; 6: 26.","journal-title":"Stem\u2002Cell\u2002Res Ther"},{"key":"BFcddis2016480_CR3","doi-asserted-by":"publisher","first-page":"923","DOI":"10.1161\/CIRCRESAHA.111.243147","volume":"109","author":"AR Williams","year":"2011","unstructured":"Williams AR, Hare JM . Mesenchymal stem cells: biology, pathophysiology, translational findings, and therapeutic implications for cardiac disease. Circ Res 2011; 109: 923\u2013940.","journal-title":"Circ Res"},{"key":"BFcddis2016480_CR4","doi-asserted-by":"publisher","first-page":"351","DOI":"10.3727\/000000006783981918","volume":"15","author":"N Tran","year":"2006","unstructured":"Tran N, Li Y, Maskali F, Antunes L, Maureira P, Laurens MH et al. Short-term heart retention and distribution of intramyocardial delivered mesenchymal cells within necrotic or intact myocardium. Cell Transplant 2006; 15: 351\u2013358.","journal-title":"Cell Transplant"},{"key":"BFcddis2016480_CR5","doi-asserted-by":"publisher","first-page":"979","DOI":"10.1007\/s12192-015-0627-7","volume":"20","author":"YB Chen","year":"2015","unstructured":"Chen YB, Lan YW, Chen LG, Huang TT, Choo KB, Cheng WT et al. Mesenchymal stem cell-based HSP70 promoter-driven VEGFA induction by resveratrol alleviates elastase-induced emphysema in a mouse model. Cell Stress Chaperones 2015; 20: 979\u2013989.","journal-title":"Cell Stress Chaperones"},{"key":"BFcddis2016480_CR6","doi-asserted-by":"publisher","first-page":"310928","DOI":"10.4061\/2011\/310928","volume":"2011","author":"R Mingliang","year":"2011","unstructured":"Mingliang R, Bo Z, Zhengguo W . Stem cells for cardiac repair: status, mechanisms, and new strategies. Stem Cells Int 2011; 2011: 310928.","journal-title":"Stem Cells Int"},{"key":"BFcddis2016480_CR7","doi-asserted-by":"publisher","first-page":"e7325","DOI":"10.1371\/journal.pone.0007325","volume":"4","author":"H Das","year":"2009","unstructured":"Das H, George JC, Joseph M, Das M, Abdulhameed N, Blitz A et al. Stem cell therapy with overexpressed VEGF and PDGF genes improves cardiac function in a rat infarct model. PLoS One 2009; 4: e7325.","journal-title":"PLoS One"},{"key":"BFcddis2016480_CR8","doi-asserted-by":"publisher","first-page":"85","DOI":"10.1530\/REP-09-0300","volume":"139","author":"CE Forristal","year":"2010","unstructured":"Forristal CE, Wright KL, Hanley NA, Oreffo RO, Houghton FD . Hypoxia inducible factors regulate pluripotency and proliferation in human embryonic stem cells cultured at reduced oxygen tensions. Reproduction 2010; 139: 85\u201397.","journal-title":"Reproduction"},{"key":"BFcddis2016480_CR9","doi-asserted-by":"publisher","first-page":"557","DOI":"10.1101\/gad.1399906","volume":"20","author":"KL Covello","year":"2006","unstructured":"Covello KL, Kehler J, Yu H, Gordan JD, Arsham AM, Hu CJ et al. HIF-2 regulates Oct-4: effects of hypoxia on stem cell function, embryonic development, and tumor growth. Genes Dev 2006; 20: 557\u2013570.","journal-title":"Genes Dev"},{"key":"BFcddis2016480_CR10","doi-asserted-by":"publisher","first-page":"674","DOI":"10.1002\/stem.1546","volume":"32","author":"Y Iso","year":"2014","unstructured":"Iso Y, Rao KS, Poole CN, Zaman AK, Curril I, Sobel BE et al. Priming with ligands secreted by human stromal progenitor cells promotes grafts of cardiac stem\/progenitor cells after myocardial infarction. Stem Cells 2014; 32: 674\u2013683.","journal-title":"Stem Cells"},{"key":"BFcddis2016480_CR11","doi-asserted-by":"publisher","first-page":"1132","DOI":"10.1002\/jcb.20949","volume":"99","author":"S Zhang","year":"2006","unstructured":"Zhang S, Ge J, Sun A, Xu D, Qian J, Lin J et al. Comparison of various kinds of bone marrow stem cells for the repair of infarcted myocardium: single clonally purified non-hematopoietic mesenchymal stem cells serve as a superior source. J Cell Biochem 2006; 99: 1132\u20131147.","journal-title":"J Cell Biochem"},{"key":"BFcddis2016480_CR12","doi-asserted-by":"publisher","first-page":"pii: e003714","DOI":"10.1161\/JAHA.116.003714","volume":"5","author":"AP Hnatiuk","year":"2016","unstructured":"Hnatiuk AP, Ong SG, Olea FD, Locatelli P, Riegler J, Lee WH et al. Allogeneic mesenchymal stromal cells overexpressing mutant human hypoxia-inducible factor 1-\u03b1 (HIF1-\u03b1 in an ovine model of acute myocardial infarction. J Am Heart Assoc 2016; 5: pii: e003714.","journal-title":"J Am Heart Assoc"},{"key":"BFcddis2016480_CR13","doi-asserted-by":"publisher","first-page":"1131","DOI":"10.1016\/j.exphem.2010.08.003","volume":"38","author":"A Abdel-Latif","year":"2010","unstructured":"Abdel-Latif A, Zuba-Surma EK, Ziada KM, Kucia M, Cohen DA, Kaplan AM et al. Evidence of mobilization of pluripotent stem cells into peripheral blood of patients with myocardial ischemia. Exp Hematol 2010; 38: 1131\u20131142.","journal-title":"Exp Hematol"},{"key":"BFcddis2016480_CR14","doi-asserted-by":"publisher","first-page":"1952","DOI":"10.1002\/stem.748","volume":"29","author":"JA Alva","year":"2011","unstructured":"Alva JA, Lee GE, Escobar EE, Pyle AD . Phosphatase and tensin homolog regulates the pluripotent state and lineage fate choice in human embryonic stem cells. Stem Cells 2011; 29: 1952\u20131962.","journal-title":"Stem Cells"},{"key":"BFcddis2016480_CR15","doi-asserted-by":"publisher","first-page":"138","DOI":"10.1007\/s12265-010-9254-y","volume":"4","author":"W Wojakowski","year":"2011","unstructured":"Wojakowski W, Kucia M, Liu R, Zuba-Surma E, Jadczyk T, Bachowski R et al. Circulating very small embryonic-like stem cells in cardiovascular disease. J Cardiovasc Transl Res 2011; 4: 138\u2013144.","journal-title":"J Cardiovasc Transl Res"},{"key":"BFcddis2016480_CR16","doi-asserted-by":"publisher","first-page":"148","DOI":"10.1016\/j.biomaterials.2016.06.020","volume":"102","author":"TC Tseng","year":"2016","unstructured":"Tseng TC, Hsieh FY, Dai NT, Hsu SH . Substrate-mediated reprogramming of human fibroblasts into neural crest stem-like cells and their applications in neural repair. Biomaterials 2016; 102: 148\u2013161.","journal-title":"Biomaterials"},{"key":"BFcddis2016480_CR17","doi-asserted-by":"publisher","first-page":"122","DOI":"10.1186\/s12958-015-0121-1","volume":"13","author":"P Kurkure","year":"2015","unstructured":"Kurkure P, Prasad M, Dhamankar V, Bakshi G . Very small embryonic-like stem cells (VSELs) detected in azoospermic testicular biopsies of adult survivors of childhood cancer. Reprod Biol Endocrinol 2015; 13: 122.","journal-title":"Reprod Biol Endocrinol"},{"key":"BFcddis2016480_CR18","doi-asserted-by":"publisher","first-page":"125","DOI":"10.1007\/978-1-4614-5894-4_9","volume":"777","author":"MZ Ratajczak","year":"2013","unstructured":"Ratajczak MZ, Mierzejewska K, Ratajczak J, Kucia M . CD133 expression strongly correlates with the phenotype of very small embryonic-\/epiblast-like stem cells. Adv Exp Med Biol 2013; 777: 125\u2013141.","journal-title":"Adv Exp Med Biol"},{"key":"BFcddis2016480_CR19","doi-asserted-by":"publisher","first-page":"622","DOI":"10.1089\/scd.2012.0327","volume":"22","author":"AM Havens","year":"2013","unstructured":"Havens AM, Shiozawa Y, Jung Y, Sun H, Wang J, McGee S et al. Human very small embryonic-like cells generate skeletal structures, in vivo. Stem Cells Dev 2013; 22: 622\u2013630.","journal-title":"Stem Cells Dev"},{"key":"BFcddis2016480_CR20","doi-asserted-by":"publisher","first-page":"1711","DOI":"10.1002\/ibd.22875","volume":"18","author":"W Marlicz","year":"2012","unstructured":"Marlicz W, Zuba-Surma E, Kucia M, Blogowski W, Starzynska T, Ratajczak MZ . Various types of stem cells, including a population of very small embryonic-like stem cells, are mobilized into peripheral blood in patients with Crohn's disease. Inflamm Bowel Dis 2012; 18: 1711\u20131722.","journal-title":"Inflamm Bowel Dis"},{"key":"BFcddis2016480_CR21","doi-asserted-by":"publisher","first-page":"22","DOI":"10.1186\/scrt410","volume":"5","author":"B Huang","year":"2014","unstructured":"Huang B, Qian J, Ma J, Huang Z, Shen Y, Chen X et al. Myocardial transfection of hypoxia-inducible factor-1\u03b1 and co-transplantation of mesenchymal stem cells enhance cardiac repair in rats with experimentalmyocardial infarction. Stem Cell\u2002Res Ther 2014; 5: 22.","journal-title":"Stem Cell\u2002Res Ther"},{"key":"BFcddis2016480_CR22","doi-asserted-by":"publisher","first-page":"e34899","DOI":"10.1371\/journal.pone.0034899","volume":"7","author":"R Danova-Alt","year":"2012","unstructured":"Danova-Alt R, Heider A, Egger D, Cross M, Alt R . Very small embryonic-like stem cells purified from umbilical cord blood lack stem cell characteristics. PLoS One 2012; 7: e34899.","journal-title":"PLoS One"},{"key":"BFcddis2016480_CR23","doi-asserted-by":"publisher","first-page":"2210","DOI":"10.1089\/ten.tea.2011.0719","volume":"8","author":"SY Lim","year":"2012","unstructured":"Lim SY, Hsiao ST, Lokmic Z, Sivakumaran P, Dusting GJ, Dilley RJ . Ischemic preconditioning promotes intrinsic vascularization and enhances survival of implanted cells in an in vivo tissue engineering model. Tissue Eng Part A 2012; 8: 2210\u20132219.","journal-title":"Tissue Eng Part A"},{"key":"BFcddis2016480_CR24","doi-asserted-by":"publisher","first-page":"2709","DOI":"10.1007\/s00018-015-1907-1","volume":"72","author":"N Woik","year":"2015","unstructured":"Woik N, Kroll J . Regulation of lung development and regeneration by the vascular system. Cell Mol Life Sci 2015; 72: 2709\u20132718.","journal-title":"Cell Mol Life Sci"},{"key":"BFcddis2016480_CR25","doi-asserted-by":"publisher","first-page":"319","DOI":"10.4161\/pri.25008","volume":"7","author":"K Donskow-\u0141ysoniewska","year":"2013","unstructured":"Donskow-\u0141ysoniewska K, Brodaczewska K, Doligalska M . Heligmosomoides polygyrus antigens inhibit the intrinsic pathway of apoptosis by overexpression of\u2002survivin\u2002and Bcl-2 protein in CD4 T cells. Prion 2013; 7: 319\u2013327.","journal-title":"Prion"},{"key":"BFcddis2016480_CR26","doi-asserted-by":"publisher","first-page":"e56","DOI":"10.1038\/emm.2013.117","volume":"45","author":"DM Shin","year":"2013","unstructured":"Shin DM, Suszynska M, Mierzejewska K, Ratajczak J, Ratajczak MZ . Very small embryonic-like stem-cell optimization of isolation protocols: an update of molecular signatures and a review of current in vivo applications. Exp Mol Med 2013; 45: e56.","journal-title":"Exp Mol Med"},{"key":"BFcddis2016480_CR27","doi-asserted-by":"publisher","first-page":"25","DOI":"10.1186\/1757-2215-7-25","volume":"7","author":"S Parte","year":"2014","unstructured":"Parte S, Bhartiya D, Patel H, Daithankar V, Chauhan A, Zaveri K et al. Dynamics associated with spontaneous differentiation of ovarian stem cells in vitro. J Ovarian Res 2014; 7: 25.","journal-title":"J Ovarian Res"},{"key":"BFcddis2016480_CR28","doi-asserted-by":"publisher","first-page":"383","DOI":"10.1006\/exnr.2001.7832","volume":"172","author":"MK Carpenter","year":"2001","unstructured":"Carpenter MK, Inokuma MS, Denham J, Mujtaba T, Chiu CP, Rao MS . Enrichment of neurons and neural precursors from human embryonic stem cells. Exp Neurol 2001; 172: 383\u2013397.","journal-title":"Exp Neurol"},{"key":"BFcddis2016480_CR29","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1089\/scd.2011.0311","volume":"21","author":"D Bhartiya","year":"2012","unstructured":"Bhartiya D, Shaikh A, Nagvenkar P, Kasiviswanathan S, Pethe P, Pawani H et al. Very small embryonic-like stem cells with maximum regenerative potential get discarded during cord blood banking and bone marrow processing for autologous stem cell therapy. Stem Cells Dev 2012; 21: 1\u20136.","journal-title":"Stem Cells Dev"},{"key":"BFcddis2016480_CR30","doi-asserted-by":"publisher","first-page":"1195","DOI":"10.1634\/stemcells.2006-0605","volume":"25","author":"S Zhang","year":"2007","unstructured":"Zhang S, Ge J, Zhao L, Qian J, Huang Z, Shen L et al. Host vascular niche contributes to myocardial repair induced by intracoronary bone marrow stem cells infusion in infarcted swine hearts. Stem Cells 2007; 25: 1195\u20131203.","journal-title":"Stem Cells"}],"container-title":["Cell Death &amp; Disease"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/cddis2016480.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/cddis2016480","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/cddis2016480.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,1,2]],"date-time":"2023-01-02T14:57:07Z","timestamp":1672671427000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/cddis2016480"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,1,12]]},"references-count":30,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2018,1]]}},"alternative-id":["BFcddis2016480"],"URL":"https:\/\/doi.org\/10.1038\/cddis.2016.480","relation":{},"ISSN":["2041-4889"],"issn-type":[{"value":"2041-4889","type":"electronic"}],"subject":[],"published":{"date-parts":[[2017,1,12]]},"assertion":[{"value":"5 September 2016","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"8 December 2016","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"13 December 2016","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"12 January 2017","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no conflict of interest.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}