{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:47:23Z","timestamp":1787028443567,"version":"build-2736575974"},"reference-count":30,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2021,2,1]],"date-time":"2021-02-01T00:00:00Z","timestamp":1612137600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Human bone marrow-derived mesenchymal stem cells (BM-MSCs), represented as a population of adult stem cells, have long been considered as one of the most promising sources for cell-based cardiac regenerative therapy. However, their clinical use has been significantly hampered by low survival and poor retention following administration into failing hearts. Here, to improve the therapeutic effectiveness of BM-MSCs, we examined a novel therapeutic platform named in situ preconditioning in a rat myocardial infarction (MI) model. In situ preconditioning was induced by a combinatory treatment of BM-MSCs with genetically engineered hepatocyte growth factor-expressing MSCs (HGF-eMSCs) and heart-derived extracellular matrix (hdECM) hydrogel. Subsequently, our results demonstrated that in situ preconditioning with cell mixture substantially improved the survival\/retention of BM-MSCs in the MI-induced rat hearts. Enhanced retention of BM-MSCs ultimately led to a significant cardiac function improvement, which was derived from the protection of myocardium and enhancement of vessel formation in the MI hearts. The results provide compelling evidence that in situ preconditioning devised to improve the therapeutic potential of BM-MSCs can be an effective strategy to achieve cardiac repair of MI hearts.<\/jats:p>","DOI":"10.3390\/ijms22031449","type":"journal-article","created":{"date-parts":[[2021,2,1]],"date-time":"2021-02-01T11:40:48Z","timestamp":1612179648000},"page":"1449","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["In Situ Preconditioning of Human Mesenchymal Stem Cells Elicits Comprehensive Cardiac Repair Following Myocardial Infarction"],"prefix":"10.3390","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7425-8192","authenticated-orcid":false,"given":"Woo-Sup","family":"Sim","sequence":"first","affiliation":[{"name":"Department of Biomedicine &amp; Health Sciences, The Catholic University of Korea, 222 Banpo-daero, Seocho-gu, Seoul 137701, Korea"},{"name":"Division of Cardiology, Department of Internal Medicine, Seoul St. Mary\u2019s Hospital, The Catholic University of Korea, 222 Banpo-daero, Seocho-gu, Seoul 137701, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5299-2521","authenticated-orcid":false,"given":"Bong-Woo","family":"Park","sequence":"additional","affiliation":[{"name":"Department of Biomedicine &amp; Health Sciences, The Catholic University of Korea, 222 Banpo-daero, Seocho-gu, Seoul 137701, Korea"},{"name":"Division of Cardiology, Department of Internal Medicine, Seoul St. Mary\u2019s Hospital, The Catholic University of Korea, 222 Banpo-daero, Seocho-gu, Seoul 137701, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0805-5439","authenticated-orcid":false,"given":"Kiwon","family":"Ban","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, City University of Hong Kong, Tat Chee Avenue, Kowloon, Hong Kong, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8009-9546","authenticated-orcid":false,"given":"Hun-Jun","family":"Park","sequence":"additional","affiliation":[{"name":"Department of Biomedicine &amp; Health Sciences, The Catholic University of Korea, 222 Banpo-daero, Seocho-gu, Seoul 137701, Korea"},{"name":"Division of Cardiology, Department of Internal Medicine, Seoul St. Mary\u2019s Hospital, The Catholic University of Korea, 222 Banpo-daero, Seocho-gu, Seoul 137701, Korea"},{"name":"Cell Death Disease Research Center, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,2,1]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2053","DOI":"10.1056\/NEJMra1606915","article-title":"Acute Myocardial Infarction","volume":"376","author":"Anderson","year":"2017","journal-title":"New Engl. J. Med."},{"key":"ref_2","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":"ref_3","first-page":"267","article-title":"Fibroblast precursors in normal and irradiated mouse hematopoietic organs","volume":"4","author":"Friedenstein","year":"1976","journal-title":"Exp. Hematol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"437","DOI":"10.1007\/s00109-019-01752-6","article-title":"Exploring the roles of MSCs in infections: Focus on bacterial diseases","volume":"97","author":"Marrazzo","year":"2019","journal-title":"J. Mol. Med. (Berl)"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"14022","DOI":"10.1073\/pnas.0903201106","article-title":"Allogeneic mesenchymal stem cells restore cardiac function in chronic ischemic cardiomyopathy via trilineage differentiating capacity","volume":"106","author":"Quevedo","year":"2009","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"840","DOI":"10.1016\/j.ymthe.2006.05.016","article-title":"Mesenchymal stem cells overexpressing Akt dramatically repair infarcted myocardium and improve cardiac function despite infrequent cellular fusion or differentiation","volume":"14","author":"Noiseux","year":"2006","journal-title":"Mol. Ther."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1448","DOI":"10.3892\/mmr.2014.2378","article-title":"Bone marrow mesenchymal stem cells improve myocardial function in a swine model of acute myocardial infarction","volume":"10","author":"Zhao","year":"2014","journal-title":"Mol. Med. Rep."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1016\/j.amjcard.2004.03.034","article-title":"Effect on left ventricular function of intracoronary transplantation of autologous bone marrow mesenchymal stem cell in patients with acute myocardial infarction","volume":"94","author":"Chen","year":"2004","journal-title":"Am. J. Cardiol."},{"key":"ref_9","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_10","doi-asserted-by":"crossref","first-page":"1744","DOI":"10.1093\/eurheartj\/ehv136","article-title":"Bone marrow-derived mesenchymal stromal cell treatment in patients with severe ischaemic heart failure: A randomized placebo-controlled trial (MSC-HF trial)","volume":"36","author":"Mathiasen","year":"2015","journal-title":"Eur. Heart J."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"238","DOI":"10.1536\/ihj.16-328","article-title":"A randomized comparative study on the efficacy of intracoronary infusion of autologous bone marrow mononuclear cells and mesenchymal stem cells in patients with dilated cardiomyopathy","volume":"58","author":"Xiao","year":"2017","journal-title":"Int. Heart J."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1917","DOI":"10.1016\/j.athoracsur.2011.07.012","article-title":"Stem Cell Engraftment and Survival in the Ischemic Heart","volume":"92","author":"Wu","year":"2011","journal-title":"Ann. Thorac. Surg."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1225","DOI":"10.1016\/j.jtcvs.2008.11.001","article-title":"Tracking cardiac engraftment and distribution of implanted bone marrow cells: Comparing intra-aortic, intravenous, and intramyocardial delivery","volume":"137","author":"Li","year":"2009","journal-title":"J. Thorac. Cardiovasc. Surg."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"2118","DOI":"10.1634\/stemcells.2006-0771","article-title":"Bcl-2 engineered MSCs inhibited apoptosis and improved heart function","volume":"25","author":"Li","year":"2007","journal-title":"Stem Cells"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1093\/bmb\/ldw059","article-title":"Stem cell therapy for ischemic heart diseases","volume":"121","author":"Yu","year":"2017","journal-title":"Br. Med. Bull."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"959","DOI":"10.1517\/14712598.2013.782390","article-title":"Deferoxamine preconditioning potentiates mesenchymal stem cell homing in vitro and in streptozotocin-diabetic rats","volume":"13","author":"Najafi","year":"2013","journal-title":"Expert Opin. Biol. Ther."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1428","DOI":"10.1111\/jcmm.13492","article-title":"Preconditioning influences mesenchymal stem cell properties in vitro and in vivo","volume":"22","author":"Hu","year":"2018","journal-title":"J. Cell. Mol. Med."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"762","DOI":"10.1089\/scd.2016.0332","article-title":"Low-level laser effect on proliferation, migration, and antiapoptosis of mesenchymal stem cells","volume":"26","author":"Yin","year":"2017","journal-title":"Stem Cells Dev."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"130","DOI":"10.1016\/j.lfs.2016.02.066","article-title":"Pulsed electromagnetic fields promote survival and neuronal differentiation of human BM-MSCs","volume":"151","author":"Urnukhsaikhan","year":"2016","journal-title":"Life Sci."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1186\/s12967-017-1144-5","article-title":"A novel cytoprotective peptide protects mesenchymal stem cells against mitochondrial dysfunction and apoptosis induced by starvation via Nrf2\/Sirt3\/FoxO3a pathway","volume":"15","author":"Wang","year":"2017","journal-title":"J. Transl. Med."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"2261","DOI":"10.2147\/IJN.S71925","article-title":"Silica nanoparticles increase human adipose tissue-derived stem cell proliferation through ERK1\/2 activation","volume":"10","author":"Kim","year":"2015","journal-title":"Int. J. Nanomed."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"2198","DOI":"10.1161\/01.CIR.0000163546.27639.AA","article-title":"Monitoring of Bone Marrow Cell Homing Into the Infarcted Human Myocardium","volume":"111","author":"Hofmann","year":"2005","journal-title":"Circulation"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"902","DOI":"10.1016\/S0891-5849(01)00663-3","article-title":"Hepatocyte growth factor protects cardiac myocytes against oxidative stress-induced apoptosis","volume":"31","author":"Kitta","year":"2001","journal-title":"Free Radic. Biol. Med."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1016\/S0008-6363(01)00272-3","article-title":"A potential cardioprotective role of hepatocyte growth factor in myocardial infarction in rats","volume":"51","author":"Ueda","year":"2001","journal-title":"Cardiovasc. Res."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1016\/j.biomaterials.2014.12.021","article-title":"Delivery of an engineered HGF fragment in an extracellular matrix-derived hydrogel prevents negative LV remodeling post-myocardial infarction","volume":"45","author":"Sonnenberg","year":"2015","journal-title":"Biomaterials"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1511","DOI":"10.1172\/JCI10226","article-title":"Myocardial protection from ischemia\/reperfusion injury by endogenous and exogenous HGF","volume":"106","author":"Nakamura","year":"2000","journal-title":"J. Clin. Investig."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"15826","DOI":"10.1038\/s41598-017-15870-z","article-title":"Treatment of Myocardial Infarction with Gene-modified Mesenchymal Stem Cells in a Small Molecular Hydrogel","volume":"7","author":"Wu","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"eaay6994","DOI":"10.1126\/sciadv.aay6994","article-title":"In vivo priming of human mesenchymal stem cells with hepatocyte growth factor\u2013engineered mesenchymal stem cells promotes therapeutic potential for cardiac repair","volume":"6","author":"Park","year":"2020","journal-title":"Sci. Adv."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"3123","DOI":"10.1038\/s41467-019-11091-2","article-title":"Dual stem cell therapy synergistically improves cardiac function and vascular regeneration following myocardial infarction","volume":"10","author":"Park","year":"2019","journal-title":"Nat. Commun."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"2041731420953413","DOI":"10.1177\/2041731420953413","article-title":"In vivo combinatory gene therapy synergistically promotes cardiac function and vascular regeneration following myocardial infarction","volume":"11","author":"Lee","year":"2020","journal-title":"J. Tissue Eng."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/3\/1449\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T05:18:21Z","timestamp":1760159901000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/3\/1449"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,2,1]]},"references-count":30,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2021,2]]}},"alternative-id":["ijms22031449"],"URL":"https:\/\/doi.org\/10.3390\/ijms22031449","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,2,1]]}}}