{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,2]],"date-time":"2026-01-02T12:25:30Z","timestamp":1767356730797,"version":"3.48.0"},"reference-count":49,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2026,1,2]],"date-time":"2026-01-02T00:00:00Z","timestamp":1767312000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundations of China","doi-asserted-by":"publisher","award":["82174120"],"award-info":[{"award-number":["82174120"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Traditional Chinese Medicine Research Project of Shanghai Municipal Health Commission","award":["2024PT005"],"award-info":[{"award-number":["2024PT005"]}]},{"name":"Natural Science Foundation of Shanghai","award":["23ZR1460600"],"award-info":[{"award-number":["23ZR1460600"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Human induced pluripotent stem cells (hiPSCs) offer significant potential for differentiation and research applications in cardiovascular diseases. When induced differentiated hiPSC-derived cardiomyocytes (hiPSC-CMs) are transplanted into the infarcted myocardial region, they exhibit extremely low survival rates and unsatisfactory therapeutic effects due to ischemia, hypoxia, and immune inflammation in the surrounding environment. To address this issue, we used Panax notoginseng saponin R1 (NGR1), which has demonstrated significant protective effects in prior research, to pretreat hiPSC-CMs before transplantation. Utilizing an in vitro H2O2 oxidative stress model and a nude mouse myocardial infarction (MI) model, we investigated the mechanism through which NGR1 pretreatment enhances the therapeutic efficacy of hiPSC-CM transplantation. The results revealed that the hiPSC-CMs expressed cTnT. NGR1 did not promote the proliferation of hiPSC-CMs but instead induced elevated levels of p-Akt protein in these cells. Compared to hiPSC-CM transplantation alone, transplantation of hiPSC-CMs pretreated with NGR1 exhibited higher ejection fraction (EF) and fractional shortening (FS) values, along with reduced infarct size and collagen deposition. Additionally, there were more HNA-positive cardiomyocytes in the cardiac tissue, fewer TUNEL-positive signals, and increased VWF-positive and Lyve1-positive signals. Furthermore, the gene expression levels of VEGFC, IGF-1, and SDF-1 were higher. Therefore, NGR1 pretreatment improves the survival of transplanted hiPSC-CMs in tissues, reduces myocardial apoptosis, enhances cardiac function, decreases infarct size and collagen deposition, promotes angiogenesis and lymphangiogenesis, and stimulates paracrine secretion.<\/jats:p>","DOI":"10.3390\/ijms27010475","type":"journal-article","created":{"date-parts":[[2026,1,2]],"date-time":"2026-01-02T12:23:44Z","timestamp":1767356624000},"page":"475","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["NGR1 Pretreatment Enhances the Therapeutic Efficacy of Transplanting Cardiomyocytes Derived from Human Induced Pluripotent Stem Cells for Myocardial Infarction"],"prefix":"10.3390","volume":"27","author":[{"given":"Hao","family":"Cai","sequence":"first","affiliation":[{"name":"Department of Anatomy, School of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Meng-Ying","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Anatomy, School of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fang-Fang","family":"Mou","sequence":"additional","affiliation":[{"name":"Department of Anatomy, School of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qiang-Li","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Histoembryology, School of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhi-Rong","family":"Luo","sequence":"additional","affiliation":[{"name":"Department of Anatomy, School of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ping-Ping","family":"Lu","sequence":"additional","affiliation":[{"name":"Department of Anatomy, School of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bao-Nian","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Anatomy, School of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Liang","family":"Hu","sequence":"additional","affiliation":[{"name":"Academy of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1641-9562","authenticated-orcid":false,"given":"Hai-Dong","family":"Guo","sequence":"additional","affiliation":[{"name":"Department of Anatomy, School of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China"},{"name":"Academy of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,1,2]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2135","DOI":"10.1016\/j.jacc.2024.11.009","article-title":"2025 ACC\/AHA\/ACEP\/NAEMSP\/SCAI Guideline for the Management of Patients With Acute Coronary Syndromes: A Report of the American College of Cardiology\/American Heart Association Joint Committee on Clinical Practice Guidelines","volume":"85","author":"Rao","year":"2025","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Nicolau, A.M., Silva, P.G., Mejia, H.P.G., Granada, J.F., Kaluza, G.L., Burkhoff, D., Abizaid, T., Pileggi, B., Freire, A.F.D., and Godinho, R.R. (2025). Molecular Mechanisms of Microvascular Obstruction and Dysfunction in Percutaneous Coronary Interventions: From Pathophysiology to Therapeutics-A Comprehensive Review. Int. J. Mol. Sci., 26.","DOI":"10.3390\/ijms26146835"},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Wang, Y., Xue, Y., and Guo, H.D. (2022). Intervention effects of traditional Chinese medicine on stem cell therapy of myocardial infarction. Front. Pharmacol., 13.","DOI":"10.3389\/fphar.2022.1013740"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1007\/978-1-0716-0668-1_10","article-title":"Generation of Human Induced Pluripotent Stem Cells and Differentiation into Cardiomyocytes","volume":"2158","author":"Han","year":"2021","journal-title":"Methods Mol. Biol."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Sugiura, T., Shahannaz, D.C., and Ferrell, B.E. (2024). Current Status of Cardiac Regenerative Therapy Using Induced Pluripotent Stem Cells. Int. J. Mol. Sci., 25.","DOI":"10.20944\/preprints202404.1796.v1"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1016\/j.ymthe.2022.08.012","article-title":"Transient secretion of VEGF protein from transplanted hiPSC-CMs enhances engraftment and improves rat heart function post MI","volume":"31","author":"Ai","year":"2023","journal-title":"Mol. Ther."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1395","DOI":"10.1161\/CIRCULATIONAHA.122.061736","article-title":"Combined Treatment of Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes and Endothelial Cells Regenerate the Infarcted Heart in Mice and Non-Human Primates","volume":"148","author":"Cheng","year":"2023","journal-title":"Circulation"},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Sun, B., Wang, L., Guo, W., Chen, S., Ma, Y., and Wang, D. (2023). New treatment methods for myocardial infarction. Front. Cardiovasc. Med., 10.","DOI":"10.3389\/fcvm.2023.1251669"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1016\/j.cjtee.2022.06.008","article-title":"Pharmacological properties and mechanisms of Notoginsenoside R1 in ischemia-reperfusion injury","volume":"26","author":"Zhu","year":"2023","journal-title":"Chin. J. Traumatol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1366","DOI":"10.1038\/s41401-023-01057-y","article-title":"Notoginsenoside R1 protects against myocardial ischemia\/reperfusion injury in mice via suppressing TAK1-JNK\/p38 signaling","volume":"44","author":"Zeng","year":"2023","journal-title":"Acta Pharmacol. Sin."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"102384","DOI":"10.1016\/j.redox.2022.102384","article-title":"Notoginsenoside R1-loaded mesoporous silica nanoparticles targeting the site of injury through inflammatory cells improves heart repair after myocardial infarction","volume":"54","author":"Li","year":"2022","journal-title":"Redox Biol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"419","DOI":"10.1186\/s13287-024-04039-x","article-title":"Pretreatment with Notoginsenoside R1 enhances the efficacy of neonatal rat mesenchymal stem cell transplantation in model of myocardial infarction through regulating PI3K\/Akt\/FoxO1 signaling pathways","volume":"15","author":"Cai","year":"2024","journal-title":"Stem Cell Res. Ther."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"538","DOI":"10.1016\/j.ijcard.2014.08.104","article-title":"Transplantation of salvianolic acid B pretreated mesenchymal stem cells improves cardiac function in rats with myocardial infarction through angiogenesis and paracrine mechanisms","volume":"177","author":"Guo","year":"2014","journal-title":"Int. J. Cardiol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"bio059016","DOI":"10.1242\/bio.059016","article-title":"Morpho-functional comparison of differentiation protocols to create iPSC-derived cardiomyocytes","volume":"11","author":"Nijak","year":"2022","journal-title":"Biol. Open"},{"key":"ref_15","first-page":"244","article-title":"Progress in preclinical research on induced pluripotent stem cell therapy for acute myocardial infarction","volume":"53","author":"Cai","year":"2024","journal-title":"Zhejiang Da Xue Xue Bao Yi Xue Ban"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1016\/j.omtm.2019.12.015","article-title":"Human iPSC-Derived Neural Crest Stem Cells Exhibit Low Immunogenicity","volume":"16","author":"Mehler","year":"2020","journal-title":"Mol. Ther. Methods Clin. Dev."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"100026","DOI":"10.1016\/j.xpro.2020.100026","article-title":"Subtype-Directed Differentiation of Human iPSCs into Atrial and Ventricular Cardiomyocytes","volume":"1","author":"Kleinsorge","year":"2020","journal-title":"STAR Protoc."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"123418","DOI":"10.1016\/j.biomaterials.2025.123418","article-title":"In vivo assessment of iPSC-cardiomyocyte loaded auxetic cardiac patches following chronic myocardial infarction","volume":"323","author":"Brazhkina","year":"2025","journal-title":"Biomaterials"},{"key":"ref_19","first-page":"487","article-title":"Biocompatibility of extracellular matrix hydrogel with human iPSCs differentiated cardiomyocytes","volume":"49","author":"Fan","year":"2021","journal-title":"Zhonghua Xin Xue Guan Bing Za Zhi"},{"key":"ref_20","first-page":"206","article-title":"Dual human iPSC-derived cardiac lineage cell-seeding extracellular matrix patches promote regeneration and long-term repair of infarcted hearts","volume":"28","author":"Jiang","year":"2023","journal-title":"Bioact. Mater."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Wang, Y., Shou, X., Fan, Z., Cui, J., Xue, D., and Wu, Y. (2022). A Systematic Review and Meta-Analysis of Phytoestrogen Protects Against Myocardial Ischemia\/Reperfusion Injury: Pre-Clinical Evidence From Small Animal Studies. Front. Pharmacol., 13.","DOI":"10.3389\/fphar.2022.847748"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1016\/j.freeradbiomed.2020.02.032","article-title":"Tanshinone IIA alleviates blast-induced inflammation, oxidative stress and apoptosis in mice partly by inhibiting the PI3K\/Akt\/FoxO1 signaling pathway","volume":"152","author":"Liu","year":"2020","journal-title":"Free Radic. Biol. Med."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"105656","DOI":"10.3748\/wjg.v31.i26.105656","article-title":"Kushenol I combats ulcerative colitis via intestinal barrier preservation and gut microbiota optimization","volume":"31","author":"He","year":"2025","journal-title":"World J. Gastroenterol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"989","DOI":"10.1007\/s00592-022-01883-2","article-title":"Diabetic sarcopenia: Metabolic and molecular appraisal","volume":"59","author":"Giha","year":"2022","journal-title":"Acta Diabetol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"9281481","DOI":"10.1155\/2019\/9281481","article-title":"Curculigoside Protects against Excess-Iron-Induced Bone Loss by Attenuating Akt-FoxO1-Dependent Oxidative Damage to Mice and Osteoblastic MC3T3-E1 Cells","volume":"2019","author":"Zhang","year":"2019","journal-title":"Oxid. Med. Cell Longev."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1193","DOI":"10.1016\/j.jcmg.2022.02.008","article-title":"Coronary Flow Assessment Using 3-Dimensional Ultrafast Ultrasound Localization Microscopy","volume":"15","author":"Demeulenaere","year":"2022","journal-title":"JACC Cardiovasc. Imaging"},{"key":"ref_27","first-page":"100215","article-title":"Critical role of the coronary microvasculature in heart disease: From pathologic driving force to \u201cinnocent\u201d bystander","volume":"22","author":"Prakash","year":"2022","journal-title":"Am. Heart J. Plus"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"553","DOI":"10.1681\/ASN.2020050717","article-title":"Endothelial-Derived miR-17 approximately 92 Promotes Angiogenesis to Protect against Renal Ischemia-Reperfusion Injury","volume":"32","author":"Chiba","year":"2021","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"368","DOI":"10.1038\/s41569-020-00489-x","article-title":"The evolving cardiac lymphatic vasculature in development, repair and regeneration","volume":"18","author":"Klaourakis","year":"2021","journal-title":"Nat. Rev. Cardiol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"e70043","DOI":"10.1111\/acel.70043","article-title":"Exercise-Induced Cardiac Lymphatic Remodeling Mitigates Inflammation in the Aging Heart","volume":"24","author":"Roh","year":"2025","journal-title":"Aging Cell"},{"key":"ref_31","first-page":"101204","article-title":"Role of Lymphatics in Heart Failure","volume":"2","author":"Salah","year":"2023","journal-title":"J. Soc. Cardiovasc. Angiogr. Interv."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"e58376","DOI":"10.7554\/eLife.58376","article-title":"Lymphangiogenic therapy prevents cardiac dysfunction by ameliorating inflammation and hypertension","volume":"9","author":"Song","year":"2020","journal-title":"Elife"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"107605","DOI":"10.1016\/j.carpath.2024.107605","article-title":"Neovascularization of native cardiac valves, and correlation with histopathologic, clinical, and radiologic features","volume":"69","author":"Sekulic","year":"2024","journal-title":"Cardiovasc. Pathol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1007\/s00395-023-00997-0","article-title":"Endothelial ILK induces cardioprotection by preventing coronary microvascular dysfunction and endothelial-to-mesenchymal transition","volume":"118","author":"Reventun","year":"2023","journal-title":"Basic. Res. Cardiol."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Shimizu, Y., Luo, H., and Murohara, T. (2024). Disease-Specific Alteration of Cardiac Lymphatics: A Review from Animal Disease Models to Clinics. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms251910656"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"4","DOI":"10.26508\/lsa.202000666","article-title":"BACH family members regulate angiogenesis and lymphangiogenesis by modulating VEGFC expression","volume":"3","author":"Cohen","year":"2020","journal-title":"Life Sci. Alliance"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"348","DOI":"10.2174\/1574888X17666220318144608","article-title":"Intravenous Injection of SDF-1alpha-overexpressing Bone Marrow Mesenchymal Stem Cells has a Potential Protective Effect on Myocardial Ischemia in Mice","volume":"17","author":"Wang","year":"2022","journal-title":"Curr. Stem Cell Res. Ther."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1016\/j.bbrc.2022.01.030","article-title":"Stromal cell-derived factor-1 exerts opposing roles through CXCR4 and CXCR7 in angiotensin II-induced adventitial remodeling","volume":"594","author":"Song","year":"2022","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1016\/j.actbio.2021.06.038","article-title":"Sodium alginate\/collagen\/stromal cell-derived factor-1 neural scaffold loaded with BMSCs promotes neurological function recovery after traumatic brain injury","volume":"131","author":"Ma","year":"2021","journal-title":"Acta Biomater."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"344","DOI":"10.1007\/s12015-020-09952-1","article-title":"Rapamycin-Preactivated Autophagy Enhances Survival and Differentiation of Mesenchymal Stem Cells After Transplantation into Infarcted Myocardium","volume":"16","author":"Li","year":"2020","journal-title":"Stem Cell Rev. Rep."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"118977","DOI":"10.1016\/j.lfs.2020.118977","article-title":"Thyroid hormone mediates cardioprotection against postinfarction remodeling and dysfunction through the IGF-1\/PI3K\/AKT signaling pathway","volume":"267","author":"Zeng","year":"2021","journal-title":"Life Sci."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Xue, Z., Yang, D., Jin, Z., Li, Y., Yu, Y., Zhao, X., Huang, Y., Jia, S., Zhang, T., and Huang, G. (2025). IGF-1 secreted by mesenchymal stem cells affects the function of lymphatic endothelial progenitor cells: A potential strategy for the treatment of lymphedema. Front. Genet., 16.","DOI":"10.3389\/fgene.2025.1584095"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"29","DOI":"10.3892\/ijmm.2021.4862","article-title":"Resveratrol protects against myocardial ischemic injury via the inhibition of NF-kappaB-dependent inflammation and the enhancement of antioxidant defenses","volume":"47","author":"He","year":"2021","journal-title":"Int. J. Mol. Med."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1016\/j.yjmcc.2021.12.007","article-title":"Systematic transcriptomic and phenotypic characterization of human and murine cardiac myocyte cell lines and primary cardiomyocytes reveals serious limitations and low resemblances to adult cardiac phenotype","volume":"165","author":"Onodi","year":"2022","journal-title":"J. Mol. Cell Cardiol."},{"key":"ref_45","first-page":"766","article-title":"Advances in Hypertrophic Cardiomyopathy Disease Modelling Using hiPSC-Derived Cardiomyocytes","volume":"40","author":"Dababneh","year":"2024","journal-title":"Can. J. Cardiol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"e15315","DOI":"10.15252\/emmm.202115315","article-title":"Development of allogeneic iPS cell-based therapy: From bench to bedside","volume":"15","author":"McKenna","year":"2023","journal-title":"EMBO Mol. Med."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"e1101","DOI":"10.1002\/cpz1.1101","article-title":"Simultaneous Optical Imaging of Action Potentials and Calcium Transients in Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes","volume":"4","author":"Yang","year":"2024","journal-title":"Curr. Protoc."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1038\/s42003-023-04674-9","article-title":"A dynamic clamping approach using in silico IK1 current for discrimination of chamber-specific hiPSC-derived cardiomyocytes","volume":"6","author":"Altomare","year":"2023","journal-title":"Commun. Biol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"162","DOI":"10.1038\/nprot.2012.150","article-title":"Directed cardiomyocyte differentiation from human pluripotent stem cells by modulating Wnt\/beta-catenin signaling under fully defined conditions","volume":"8","author":"Lian","year":"2013","journal-title":"Nat. Protoc."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/1\/475\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,2]],"date-time":"2026-01-02T12:24:16Z","timestamp":1767356656000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/1\/475"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,1,2]]},"references-count":49,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,1]]}},"alternative-id":["ijms27010475"],"URL":"https:\/\/doi.org\/10.3390\/ijms27010475","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,1,2]]}}}