{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,16]],"date-time":"2026-03-16T18:19:51Z","timestamp":1773685191778,"version":"3.50.1"},"reference-count":23,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,6,9]],"date-time":"2021-06-09T00:00:00Z","timestamp":1623196800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100010905","name":"Major Research Plan","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100010905","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cell Dev. Biol."],"abstract":"<jats:sec><jats:title>Objective<\/jats:title><jats:p>The actin-sequestering proteins, thymosin beta-4 (T\u03b24) and hypoxia-inducible factor (HIF)-1\u03b1, are known to be associated with angiogenesis after myocardial infarction (MI). Herein, we aimed to identify the mechanism of HIF-1\u03b1 induction by T\u03b24 and investigate the effects of bone marrow mesenchymal stromal cells (BMMSCs) transfected with the T\u03b24 gene (<jats:italic>TMSB4<\/jats:italic>) in a rat model of MI.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Rat BMMSCs were isolated, cultured, and transfected with the <jats:italic>TMSB4<\/jats:italic> gene by using the lentivirus-mediated method. Rats with surgically induced MI were randomly divided into three groups (<jats:italic>n<\/jats:italic> = 9\/group); after 1 week, the rats were injected at the heart infarcted border zone with TMSB4-overexpressed BMMSCs (BMMSC-TMSB4<jats:sup><jats:italic>O<\/jats:italic><jats:italic>E<\/jats:italic><\/jats:sup>), wild-type BMMSCs that expressed normal levels of TMSB4 (BMMSC-TMSB4<jats:sup><jats:italic>W<\/jats:italic><jats:italic>T<\/jats:italic><\/jats:sup>), or medium (MI). The fourth group of animals (<jats:italic>n<\/jats:italic> = 9) underwent all surgical procedures necessary for MI induction except for the ligation step (Sham). Four weeks after the injection, heart function was measured using transthoracic echocardiography. Infarct size was calculated by TTC staining, and collagen volume was measured by Masson staining. Angiogenesis in the infarcted heart area was evaluated by CD31 immunofluorescence histochemistry. <jats:italic>In vitro<\/jats:italic> experiments were carried out to observe the effect of exogenous T\u03b24 on HIF-1\u03b1 and explore the various possible mechanism(s).<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p><jats:italic>In vivo<\/jats:italic> experiments showed that vascular density 4 weeks after treatment was about twofold higher in BMMSC-TMSB4<jats:sup><jats:italic>O<\/jats:italic><jats:italic>E<\/jats:italic><\/jats:sup>-treated animals than in BMMSC-TMSB4<jats:sup><jats:italic>W<\/jats:italic><jats:italic>T<\/jats:italic><\/jats:sup>-treated animals (<jats:italic>p<\/jats:italic> &amp;lt; 0.05). The cardiac function and infarct size significantly improved in both cell-treatment groups compared to controls. Notably, the cardiac function and infarct size were most prominent in BMMSC-TMSB4<jats:sup><jats:italic>O<\/jats:italic><jats:italic>E<\/jats:italic><\/jats:sup>-treated animals (both <jats:italic>p<\/jats:italic> &amp;lt; 0.05). HIF-1\u03b1 and phosphorylated HIF-1\u03b1 (p-HIF-1\u03b1) <jats:italic>in vitro<\/jats:italic> were significantly enhanced by exogenous T\u03b24, which was nonetheless blocked by the factor-inhibiting HIF (FIH) promoter (YC-1). The expression of prolyl hydroxylase domain proteins (PHD) was decreased upon treatment with T\u03b24 and further decreased with the combined treatment of T\u03b24 and FG-4497 (a specific PHD inhibitor).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>TMSB4-transfected BMMSCs might significantly improve recovery from myocardial ischemia and promote the generation of HIF-1\u03b1 and p-HIF-1\u03b1 <jats:italic>via<\/jats:italic> the AKT pathway, and inhibit the degradation of HIF-1\u03b1 <jats:italic>via<\/jats:italic> the PHD and FIH pathways.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fcell.2021.670913","type":"journal-article","created":{"date-parts":[[2021,6,9]],"date-time":"2021-06-09T11:15:13Z","timestamp":1623237313000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":8,"title":["TMSB4 Overexpression Enhances the Potency of Marrow Mesenchymal Stromal Cells for Myocardial Repair"],"prefix":"10.3389","volume":"9","author":[{"given":"Shiyuan","family":"Tang","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chengming","family":"Fan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chukwuemeka Daniel","family":"Iroegbu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wenwu","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhigong","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ming","family":"Wu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wangping","family":"Chen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaoming","family":"Wu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jun","family":"Peng","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhihong","family":"Li","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jinfu","family":"Yang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2021,6,9]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"95","DOI":"10.1016\/j.healun.2010.08.023","article-title":"Mesenchymal stem cell conditioned media attenuates in vitro and ex vivo myocardial reperfusion injury.","volume":"30","author":"Angoulvant","year":"2011","journal-title":"J. Heart Lung Transplant."},{"key":"B2","doi-asserted-by":"publisher","first-page":"1710","DOI":"10.1126\/science.1174381","article-title":"MicroRNA-92a controls angiogenesis and functional recovery of ischemic tissues in mice.","volume":"324","author":"Bonauer","year":"2009","journal-title":"Science"},{"key":"B3","doi-asserted-by":"publisher","first-page":"1055","DOI":"10.1242\/jcs.035022","article-title":"HIF at a glance.","volume":"122","author":"Brahimi-Horn","year":"2009","journal-title":"J. Cell Sci."},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.132796","article-title":"Myocardial protection by nanomaterials formulated with CHIR99021 and FGF1.","volume":"5","author":"Fan","year":"","journal-title":"JCI Insight"},{"key":"B5","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.yjmcc.2020.03.003","article-title":"CHIR99021 and fibroblast growth factor 1 enhance the regenerative potency of human cardiac muscle patch after myocardial infarction in mice.","volume":"141","author":"Fan","year":"","journal-title":"J. Mol. Cell. Cardiol."},{"key":"B6","doi-asserted-by":"publisher","first-page":"121","DOI":"10.1080\/14712598.2018.1490409","article-title":"Thymosin beta4-mediated protective effects in the heart.","volume":"18","author":"Hinkel","year":"2018","journal-title":"Expert Opin. Biol. Ther."},{"key":"B7","doi-asserted-by":"publisher","first-page":"933","DOI":"10.1161\/CIRCRESAHA.113.300215","article-title":"Protein engineering for cardiovascular therapeutics: untapped potential for cardiac repair.","volume":"113","author":"Jay","year":"2013","journal-title":"Circ. Res."},{"key":"B8","doi-asserted-by":"publisher","first-page":"1244","DOI":"10.1016\/j.bbamcr.2010.07.005","article-title":"Thymosin beta4 induces the expression of vascular endothelial growth factor (VEGF) in a hypoxia-inducible factor (HIF)-1alpha-dependent manner.","volume":"1803","author":"Jo","year":"2010","journal-title":"Biochim. Biophys. Acta"},{"key":"B9","doi-asserted-by":"publisher","first-page":"140","DOI":"10.1038\/nm.3778","article-title":"Myeloid-derived growth factor (C19orf10) mediates cardiac repair following myocardial infarction.","volume":"21","author":"Korf-Klingebiel","year":"2015","journal-title":"Nat. Med."},{"key":"B10","doi-asserted-by":"publisher","first-page":"1128","DOI":"10.1016\/j.jtcvs.2017.09.106","article-title":"Heart regeneration: the endothelial cell comes first.","volume":"155","author":"Mathison","year":"2018","journal-title":"J. Thorac. Cardiovasc. Surg."},{"key":"B11","doi-asserted-by":"publisher","first-page":"79","DOI":"10.1111\/j.1749-6632.2012.06657.x","article-title":"Thymosin beta4 stabilizes hypoxia-inducible factor-1alpha protein in an oxygen-independent manner.","volume":"1269","author":"Ock","year":"2012","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"B12","doi-asserted-by":"publisher","first-page":"91","DOI":"10.1161\/CIRCRESAHA.116.303577","article-title":"The biological basis for cardiac repair after myocardial infarction: from inflammation to fibrosis.","volume":"119","author":"Prabhu","year":"2016","journal-title":"Circ. Res."},{"key":"B13","doi-asserted-by":"publisher","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":"B14","doi-asserted-by":"publisher","first-page":"20399","DOI":"10.1073\/pnas.0911921106","article-title":"Synergistic effect of HIF-1alpha gene therapy and HIF-1-activated bone marrow-derived angiogenic cells in a mouse model of limb ischemia.","volume":"106","author":"Rey","year":"2009","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"B15","doi-asserted-by":"publisher","first-page":"177","DOI":"10.1038\/nature05383","article-title":"Thymosin beta4 induces adult epicardial progenitor mobilization and neovascularization.","volume":"445","author":"Smart","year":"","journal-title":"Nature"},{"key":"B16","doi-asserted-by":"publisher","first-page":"229","DOI":"10.1007\/s10456-007-9077-x","article-title":"Thymosin beta4 and angiogenesis: modes of action and therapeutic potential.","volume":"10","author":"Smart","year":"","journal-title":"Angiogenesis"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1186\/s13287-020-01881-7","article-title":"HIF-1alpha overexpression in mesenchymal stem cell-derived exosomes mediates cardioprotection in myocardial infarction by enhanced angiogenesis.","volume":"11","author":"Sun","year":"2020","journal-title":"Stem Cell. Res. Ther."},{"key":"B18","doi-asserted-by":"publisher","first-page":"4997","DOI":"10.1016\/j.ijcard.2013.07.126","article-title":"Transplantation of MSCs transfected with SHH gene ameliorates cardiac dysfunction after chronic myocardial infarction.","volume":"168","author":"Tang","year":"2013","journal-title":"Int. J. Cardiol."},{"key":"B19","doi-asserted-by":"publisher","first-page":"1880","DOI":"10.1016\/j.clinthera.2020.08.010","article-title":"Mesenchymal stem cells in cardiac repair: effects on myocytes, vasculature, and fibroblasts.","volume":"42","author":"White","year":"2020","journal-title":"Clin. Ther."},{"key":"B20","doi-asserted-by":"publisher","first-page":"204","DOI":"10.1038\/nrcardio.2010.1","article-title":"Cell therapy for the treatment of coronary heart disease: a critical appraisal.","volume":"7","author":"Wollert","year":"2010","journal-title":"Nat. Rev. Cardiol."},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1155\/2009\/128627","article-title":"Experimental study of the effects of marrow mesenchymal stem cells transfected with hypoxia-inducible factor-1alpha gene.","volume":"2009","author":"Yang","year":"2009","journal-title":"J. Biomed. Biotechnol."},{"key":"B22","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1159\/000093609","article-title":"Effects of myocardial transplantation of marrow mesenchymal stem cells transfected with vascular endothelial growth factor for the improvement of heart function and angiogenesis after myocardial infarction.","volume":"107","author":"Yang","year":"2007","journal-title":"Cardiology"},{"key":"B23","doi-asserted-by":"crossref","first-page":"S32","DOI":"10.1161\/CIRCULATIONAHA.112.000025","article-title":"Thymosin beta4 increases the potency of transplanted mesenchymal stem cells for myocardial repair.","volume":"128","author":"Ye","year":"2013","journal-title":"Circulation"}],"container-title":["Frontiers in Cell and Developmental Biology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcell.2021.670913\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,6,9]],"date-time":"2021-06-09T11:15:20Z","timestamp":1623237320000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcell.2021.670913\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,6,9]]},"references-count":23,"alternative-id":["10.3389\/fcell.2021.670913"],"URL":"https:\/\/doi.org\/10.3389\/fcell.2021.670913","relation":{},"ISSN":["2296-634X"],"issn-type":[{"value":"2296-634X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,6,9]]},"article-number":"670913"}}