{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,18]],"date-time":"2026-03-18T02:46:35Z","timestamp":1773801995456,"version":"3.50.1"},"reference-count":54,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2021,5,26]],"date-time":"2021-05-26T00:00:00Z","timestamp":1621987200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003766","name":"Ministerul Educa\u0163iei Na\u0163ionale","doi-asserted-by":"publisher","award":["PN-II-RU-TE-2014-4-1614-contract no 83\/2015"],"award-info":[{"award-number":["PN-II-RU-TE-2014-4-1614-contract no 83\/2015"]}],"id":[{"id":"10.13039\/501100003766","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003766","name":"Ministerul Educa\u0163iei Na\u0163ionale","doi-asserted-by":"publisher","award":["PN-III-P4-ID-PCCF-2016-0172-contract no 05\/18.07.2018"],"award-info":[{"award-number":["PN-III-P4-ID-PCCF-2016-0172-contract no 05\/18.07.2018"]}],"id":[{"id":"10.13039\/501100003766","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003766","name":"Ministerul Educa\u0163iei Na\u0163ionale","doi-asserted-by":"publisher","award":["PN-III-P4-ID-PCE-2020-1340-contract 122\/2021"],"award-info":[{"award-number":["PN-III-P4-ID-PCE-2020-1340-contract 122\/2021"]}],"id":[{"id":"10.13039\/501100003766","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Mesenchymal stromal cells (MSC) are promising candidates for regenerative therapy of the infarcted heart. However, poor cell retention within the transplantation site limits their potential. We hypothesized that MSC benefits could be enhanced through a dual-cell approach using jointly endothelial colony forming cells (ECFC) and MSC. To assess this, we comparatively evaluated the effects of the therapy with MSC and ECFC versus MSC-only in a mouse model of myocardial infarction. Heart function was assessed by echocardiography, and the molecular crosstalk between MSC and ECFC was evaluated in vitro through direct or indirect co-culture systems. We found that dual-cell therapy improved cardiac function in terms of ejection fraction and stroke volume. In vitro experiments showed that ECFC augmented MSC effector properties by increasing Connexin 43 and Integrin alpha-5 and the secretion of healing-associated molecules. Moreover, MSC prompted the organization of ECFC into vascular networks. This indicated a reciprocal modulation in the functionality of MSC and ECFC. In conclusion, the crosstalk between MSC and ECFC augments the therapeutic properties of MSC and enhances the angiogenic properties of ECFC. Our data consolidate the dual-cell therapy as a step forward for the development of effective treatments for patients affected by myocardial infarction.<\/jats:p>","DOI":"10.3390\/ijms22115631","type":"journal-article","created":{"date-parts":[[2021,5,26]],"date-time":"2021-05-26T10:30:32Z","timestamp":1622025032000},"page":"5631","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":23,"title":["Dual Stem Cell Therapy Improves the Myocardial Recovery Post-Infarction through Reciprocal Modulation of Cell Functions"],"prefix":"10.3390","volume":"22","author":[{"given":"Sinziana","family":"Popescu","sequence":"first","affiliation":[{"name":"Institute of Cellular Biology and Pathology \u201cNicolae Simionescu\u201d, 8, B.P. Hasdeu Street, 050568 Bucharest, Romania"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2500-4078","authenticated-orcid":false,"given":"Mihai Bogdan","family":"Preda","sequence":"additional","affiliation":[{"name":"Institute of Cellular Biology and Pathology \u201cNicolae Simionescu\u201d, 8, B.P. Hasdeu Street, 050568 Bucharest, Romania"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0727-3645","authenticated-orcid":false,"given":"Catalina Iolanda","family":"Marinescu","sequence":"additional","affiliation":[{"name":"Institute of Cellular Biology and Pathology \u201cNicolae Simionescu\u201d, 8, B.P. Hasdeu Street, 050568 Bucharest, Romania"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maya","family":"Simionescu","sequence":"additional","affiliation":[{"name":"Institute of Cellular Biology and Pathology \u201cNicolae Simionescu\u201d, 8, B.P. Hasdeu Street, 050568 Bucharest, Romania"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alexandrina","family":"Burlacu","sequence":"additional","affiliation":[{"name":"Institute of Cellular Biology and Pathology \u201cNicolae Simionescu\u201d, 8, B.P. Hasdeu Street, 050568 Bucharest, Romania"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,5,26]]},"reference":[{"key":"ref_1","unstructured":"GBD 2017 Causes of Death Collaborators (2018). Global, regional, and national age-sex-specific mortality for 282 causes of death in 195 countries and territories, 1980-2017: A systematic analysis for the Global Burden of Disease Study 2017. Lancet, 392, 1736\u20131788."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"585","DOI":"10.1038\/s41569-018-0036-6","article-title":"Therapeutic approaches for cardiac regeneration and repair","volume":"15","author":"Hashimoto","year":"2018","journal-title":"Nat. Rev. Cardiol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"659","DOI":"10.1038\/s41569-018-0013-0","article-title":"Cell therapy trials for heart regeneration-lessons learned and future directions","volume":"15","author":"Menasche","year":"2018","journal-title":"Nat. Rev. Cardiol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2532","DOI":"10.1093\/eurheartj\/ehx248","article-title":"Global position paper on cardiovascular regenerative medicine","volume":"38","author":"Climent","year":"2017","journal-title":"Eur. Heart J."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1789","DOI":"10.1093\/eurheartj\/ehw113","article-title":"Position Paper of the European Society of Cardiology Working Group Cellular Biology of the Heart: Cell-based therapies for myocardial repair and regeneration in ischemic heart disease and heart failure","volume":"37","author":"Madonna","year":"2016","journal-title":"Eur. Heart J."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1016\/j.toxlet.2010.03.009","article-title":"Intra-myocardial delivery of mesenchymal stem cells ameliorates left ventricular and cardiomyocyte contractile dysfunction following myocardial infarction","volume":"195","author":"Li","year":"2010","journal-title":"Toxicol. Lett."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1186\/scrt394","article-title":"Human umbilical cord tissue-derived mesenchymal stromal cells attenuate remodeling after myocardial infarction by proangiogenic, antiapoptotic, and endogenous cell-activation mechanisms","volume":"5","author":"Mosqueira","year":"2014","journal-title":"Stem Cell Res. Ther."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"23","DOI":"10.3346\/jkms.2014.29.1.23","article-title":"A randomized, open-label, multicenter trial for the safety and efficacy of adult mesenchymal stem cells after acute myocardial infarction","volume":"29","author":"Lee","year":"2014","journal-title":"J. Korean Med. Sci."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1038\/s41536-019-0083-6","article-title":"Mesenchymal stem cell perspective: Cell biology to clinical progress","volume":"4","author":"Pittenger","year":"2019","journal-title":"NPJ Regen. Med."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"244","DOI":"10.1016\/j.stem.2012.02.005","article-title":"Harnessing the mesenchymal stem cell secretome for the treatment of cardiovascular disease","volume":"10","author":"Ranganath","year":"2012","journal-title":"Cell Stem Cell"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"13558","DOI":"10.1038\/s41598-017-13971-3","article-title":"Mesenchymal stem\/stromal cells enhance engraftment, vasculogenic and pro-angiogenic activities of endothelial colony forming cells in immunocompetent hosts","volume":"7","author":"Shafiee","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"770","DOI":"10.1038\/s41598-017-00809-1","article-title":"Endothelial colony forming cells and mesenchymal progenitor cells form blood vessels and increase blood flow in ischemic muscle","volume":"7","author":"Kang","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"643","DOI":"10.1089\/scd.2012.0273","article-title":"Factors secreted by mesenchymal stem cells and endothelial progenitor cells have complementary effects on angiogenesis in vitro","volume":"22","author":"Burlacu","year":"2013","journal-title":"Stem Cells Dev."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1080\/14653240600855905","article-title":"Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement","volume":"8","author":"Dominici","year":"2006","journal-title":"Cytotherapy"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"94","DOI":"10.1161\/CIRCIMAGING.111.966424","article-title":"Molecular imaging of mesenchymal stem cell: Mechanistic insight into cardiac repair after experimental myocardial infarction","volume":"5","author":"Wang","year":"2012","journal-title":"Circ. Cardiovasc. Imaging."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"942","DOI":"10.1016\/j.jacc.2011.11.029","article-title":"Direct comparison of different stem cell types and subpopulations reveals superior paracrine potency and myocardial repair efficacy with cardiosphere-derived cells","volume":"59","author":"Li","year":"2012","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"4294","DOI":"10.1172\/JCI64216","article-title":"Integrins protect cardiomyocytes from ischemia\/reperfusion injury","volume":"123","author":"Okada","year":"2013","journal-title":"J. Clin. Investig."},{"key":"ref_18","first-page":"92","article-title":"Altered expression of connexin 43 and related molecular partners in a pig model of left ventricular dysfunction with and without dipyrydamole therapy","volume":"95\u201396","author":"Moscato","year":"2015","journal-title":"Pharmacol. Res."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"667","DOI":"10.1016\/j.bbrc.2015.07.055","article-title":"Pre-stimulation with FGF-2 increases in vitro functional coupling of mesenchymal stem cells with cardiac cells","volume":"464","author":"Preda","year":"2015","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"218142","DOI":"10.4061\/2010\/218142","article-title":"Fibroblast growth factors: Biology, function, and application for tissue regeneration","volume":"2010","author":"Yun","year":"2010","journal-title":"J. Tissue Eng."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"e12278","DOI":"10.14814\/phy2.12278","article-title":"Fibroblast growth factor 2 is an essential cardioprotective factor in a closed-chest model of cardiac ischemia-reperfusion injury","volume":"3","author":"House","year":"2015","journal-title":"Physiol. Rep."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1007\/s10741-007-9027-0","article-title":"Fibroblast growth factor-2 and cardioprotection","volume":"12","author":"Kardami","year":"2007","journal-title":"Heart Fail. Rev."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1016\/j.biomaterials.2015.05.002","article-title":"Combinatorial approach for improving the outcome of angiogenic therapy in ischemic tissues","volume":"60","author":"Preda","year":"2015","journal-title":"Biomaterials"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"24","DOI":"10.3389\/fonc.2018.00024","article-title":"Multifaceted Role of the Urokinase-Type Plasminogen Activator (uPA) and Its Receptor (uPAR): Diagnostic, Prognostic, and Therapeutic Applications","volume":"8","author":"Mahmood","year":"2018","journal-title":"Front. Oncol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"551","DOI":"10.1517\/14728222.2016.1113260","article-title":"The urokinase-type plasminogen activator (uPA) system as a biomarker and therapeutic target in human malignancies","volume":"20","author":"Su","year":"2016","journal-title":"Expert Opin. Ther. Targets"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1016\/j.matbio.2015.03.005","article-title":"The role of TIMPs in regulation of extracellular matrix proteolysis","volume":"44\u201346","author":"Arpino","year":"2015","journal-title":"Matrix Biol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"316","DOI":"10.1038\/nature17040","article-title":"Angiocrine functions of organ-specific endothelial cells","volume":"529","author":"Rafii","year":"2016","journal-title":"Nature"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1186\/s12979-016-0080-1","article-title":"The inflammatory protein Pentraxin 3 in cardiovascular disease","volume":"13","author":"Fornai","year":"2016","journal-title":"Immun. Ageing"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"835","DOI":"10.1111\/j.1538-7836.2007.02431.x","article-title":"Insulin-like growth factor binding protein-3 induces angiogenesis through IGF-I- and SphK1-dependent mechanisms","volume":"5","author":"Granata","year":"2007","journal-title":"J. Thromb. Haemost."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1093\/jb\/mvu031","article-title":"Roles of VEGF-A signalling in development, regeneration, and tumours","volume":"156","author":"Matsumoto","year":"2014","journal-title":"J. Biochem."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"883","DOI":"10.1002\/ijc.21479","article-title":"Epidermal growth factor receptor and angiogenesis: Opportunities for combined anticancer strategies","volume":"117","author":"Giaccone","year":"2005","journal-title":"Int. J. Cancer"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"844","DOI":"10.1158\/0008-5472.CAN-12-1681","article-title":"MDA-9\/syntenin and IGFBP-2 promote angiogenesis in human melanoma","volume":"73","author":"Das","year":"2013","journal-title":"Cancer Res."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1111\/j.1749-6632.2002.tb04870.x","article-title":"Placental growth factor (PlGF) and its receptor Flt-1 (VEGFR-1): Novel therapeutic targets for angiogenic disorders","volume":"979","author":"Luttun","year":"2002","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1038\/sj.bjc.6700750","article-title":"Endothelin-1: A multifunctional molecule in cancer","volume":"88","author":"Grant","year":"2003","journal-title":"Br. J. Cancer"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1161\/CIRCRESAHA.119.311148","article-title":"The Extracellular Matrix in Ischemic and Nonischemic Heart Failure","volume":"125","author":"Frangogiannis","year":"2019","journal-title":"Circ. Res."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"276","DOI":"10.1002\/1521-4141(200101)31:1<276::AID-IMMU276>3.0.CO;2-D","article-title":"\u03b21 integrin activation on human neutrophils promotes \u03b22 integrin-mediated adhesion to fibronectin","volume":"31","author":"Mul","year":"2001","journal-title":"Eur. J. Immunol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"538","DOI":"10.1016\/j.yjmcc.2009.06.015","article-title":"Osteopontin: Role in extracellular matrix deposition and myocardial remodeling post-MI","volume":"48","author":"Singh","year":"2010","journal-title":"J. Mol. Cell Cardiol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"479","DOI":"10.1146\/annurev-physiol-012110-142250","article-title":"Role of chitin and chitinase\/chitinase-like proteins in inflammation, tissue remodeling, and injury","volume":"73","author":"Lee","year":"2011","journal-title":"Annu. Rev. Physiol."},{"key":"ref_39","doi-asserted-by":"crossref","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":"ref_40","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":"ref_41","doi-asserted-by":"crossref","first-page":"1127","DOI":"10.1080\/14712598.2017.1346080","article-title":"Cellular mechanisms underlying cardiac engraftment of stem cells","volume":"17","author":"Kanda","year":"2017","journal-title":"Expert Opin. Biol. Ther."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"6785","DOI":"10.1016\/j.biomaterials.2013.05.060","article-title":"Transdermal regulation of vascular network bioengineering using a photopolymerizable methacrylated gelatin hydrogel","volume":"34","author":"Lin","year":"2013","journal-title":"Biomaterials"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"122","DOI":"10.3389\/fphys.2013.00122","article-title":"YKL-40 acts as an angiogenic factor to promote tumor angiogenesis","volume":"4","author":"Shao","year":"2013","journal-title":"Front. Physiol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1186\/s13287-018-0803-7","article-title":"ISL1 overexpression enhances the survival of transplanted human mesenchymal stem cells in a murine myocardial infarction model","volume":"9","author":"Xiang","year":"2018","journal-title":"Stem Cell Res. Ther."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1127","DOI":"10.1152\/physrev.00019.2015","article-title":"Rebuilding the Damaged Heart: Mesenchymal Stem Cells, Cell-Based Therapy, and Engineered Heart Tissue","volume":"96","author":"Golpanian","year":"2016","journal-title":"Physiol. Rev."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1016\/j.stem.2015.06.007","article-title":"Stem Cell Therapies in Clinical Trials: Progress and Challenges","volume":"17","author":"Trounson","year":"2015","journal-title":"Cell Stem Cell"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1177\/039463201202500110","article-title":"Endothelial progenitor cell-derived microvesicles improve neovascularization in a murine model of hindlimb ischemia","volume":"25","author":"Ranghino","year":"2012","journal-title":"Int. J. Immunopathol. Pharmacol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"H455","DOI":"10.1152\/ajpheart.00726.2015","article-title":"Stem cell-based therapies to promote angiogenesis in ischemic cardiovascular disease","volume":"310","author":"Hou","year":"2016","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"440","DOI":"10.1016\/j.atherosclerosis.2012.07.031","article-title":"Long-term clinical outcome after intramuscular transplantation of granulocyte colony stimulating factor-mobilized CD34 positive cells in patients with critical limb ischemia","volume":"224","author":"Kinoshita","year":"2012","journal-title":"Atherosclerosis"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1038\/s41536-019-0070-y","article-title":"Proteomic analysis of human mesenchymal stromal cell secretomes: A systematic comparison of the angiogenic potential","volume":"4","author":"Kehl","year":"2019","journal-title":"NPJ Regen. Med."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"660","DOI":"10.1016\/j.jacc.2007.09.059","article-title":"Strikingly different angiogenic properties of endothelial progenitor cell subpopulations: Insights from a novel human angiogenesis assay","volume":"51","author":"Sieveking","year":"2008","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_52","doi-asserted-by":"crossref","unstructured":"Donato, L., Scimone, C., Alibrandi, S., Pitruzzella, A., Scalia, F., D\u2019Angelo, R., and Sidoti, A. (2020). Possible A2E Mutagenic Effects on RPE Mitochondrial DNA from Innovative RNA-Seq Bioinformatics Pipeline. Antioxidants, 9.","DOI":"10.3390\/antiox9111158"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"575488","DOI":"10.3389\/fimmu.2020.575488","article-title":"Integrated Analysis of Transcriptome and Secretome From Umbilical Cord Mesenchymal Stromal Cells Reveal New Mechanisms for the Modulation of Inflammation and Immune Activation","volume":"11","author":"Medina","year":"2020","journal-title":"Front. Immunol."},{"key":"ref_54","first-page":"443","article-title":"Electrocardiography as a tool for validating myocardial ischemia-reperfusion procedures in mice","volume":"60","author":"Preda","year":"2010","journal-title":"Comp. Med."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/11\/5631\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T06:08:06Z","timestamp":1760162886000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/11\/5631"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,5,26]]},"references-count":54,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2021,6]]}},"alternative-id":["ijms22115631"],"URL":"https:\/\/doi.org\/10.3390\/ijms22115631","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,5,26]]}}}