{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T01:48:07Z","timestamp":1791337687939,"version":"4.3.1"},"reference-count":102,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2025,2,26]],"date-time":"2025-02-26T00:00:00Z","timestamp":1740528000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100012190","name":"Ministry of Science and Higher Education of the Russian Federation","doi-asserted-by":"publisher","award":["075-15-2021-1075"],"award-info":[{"award-number":["075-15-2021-1075"]}],"id":[{"id":"10.13039\/501100012190","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Mesenchymal stem\/stromal cells (MSCs) offer promising therapeutic potential in cell-based therapies for various diseases. However, the safety of genetically modified MSCs remains poorly understood. This study aimed to evaluate the general toxicity and safety of Wharton\u2019s Jelly-Derived MSCs (WJ-MSCs) engineered to express the antimicrobial peptide SE-33 in an animal model. Genetically modified WJ-MSCs expressing SE-33 were administered to C57BL\/6 mice at both therapeutic and excessive doses, either once or repeatedly. Animal monitoring included mortality, clinical signs, and behavioral observations. The toxicity assessment involved histopathological, hematological, and biochemical analyses of major organs and tissues, while immunotoxicity and immunogenicity were examined through humoral and cellular immune responses, macrophage phagocytic activity, and lymphocyte blast transformation. Antimicrobial efficacy was evaluated in a Staphylococcus aureus-induced pneumonia model by monitoring animal mortality and assessing bacterial load and inflammatory processes in the lungs. Mice receiving genetically modified WJ-MSCs exhibited no acute or chronic toxicity, behavioral abnormalities, or pathological changes, regardless of the dose or administration frequency. No significant immunotoxicity or alterations in immune responses were observed, and there were no notable changes in hematological or biochemical serum parameters. Infected animals treated with WJ-MSC-SE33 showed a significant reduction in bacterial load and lung inflammation and improved survival compared to control groups, demonstrating efficacy over native WJ-MSCs. Our findings suggest that WJ-MSCs expressing SE-33 are well tolerated, displaying a favorable safety profile comparable to native WJ-MSCs and potent antimicrobial activity, significantly reducing bacterial load, inflammation, and mortality in an S. aureus pneumonia model. These data support the safety profile of WJ-MSCs expressing SE-33 as a promising candidate for cell-based therapies for bacterial infections, particularly those complicated by antibiotic resistance.<\/jats:p>","DOI":"10.3390\/cells14050341","type":"journal-article","created":{"date-parts":[[2025,2,26]],"date-time":"2025-02-26T11:22:12Z","timestamp":1740568932000},"page":"341","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Preclinical Evaluation of the Safety, Toxicity and Efficacy of Genetically Modified Wharton\u2019s Jelly Mesenchymal Stem\/Stromal Cells Expressing the Antimicrobial Peptide SE-33"],"prefix":"10.3390","volume":"14","author":[{"given":"Vagif Ali oglu","family":"Gasanov","sequence":"first","affiliation":[{"name":"Koltzov Institute of Developmental Biology of Russian Academy of Sciences, Moscow 119334, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0748-9238","authenticated-orcid":false,"given":"Dmitry Alexandrovich","family":"Kashirskikh","sequence":"additional","affiliation":[{"name":"Koltzov Institute of Developmental Biology of Russian Academy of Sciences, Moscow 119334, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2096-3237","authenticated-orcid":false,"given":"Victoria Alexandrovna","family":"Khotina","sequence":"additional","affiliation":[{"name":"Koltzov Institute of Developmental Biology of Russian Academy of Sciences, Moscow 119334, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daria Mikhailovna","family":"Kuzmina","sequence":"additional","affiliation":[{"name":"Department of Normal Physiology, Privolzhsky Research Medical University of Ministry of Health of the Russian Federation, Nizhny Novgorod 603005, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sofya Yurievna","family":"Nikitochkina","sequence":"additional","affiliation":[{"name":"Koltzov Institute of Developmental Biology of Russian Academy of Sciences, Moscow 119334, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8811-0049","authenticated-orcid":false,"given":"Irina Vasilievna","family":"Mukhina","sequence":"additional","affiliation":[{"name":"Department of Normal Physiology, Privolzhsky Research Medical University of Ministry of Health of the Russian Federation, Nizhny Novgorod 603005, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5405-0212","authenticated-orcid":false,"given":"Ekaterina Andreevna","family":"Vorotelyak","sequence":"additional","affiliation":[{"name":"Koltzov Institute of Developmental Biology of Russian Academy of Sciences, Moscow 119334, Russia"},{"name":"Department of Cell Biology, Biological Faculty, Lomonosov Moscow State University, Moscow 119234, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrey Valentinovich","family":"Vasiliev","sequence":"additional","affiliation":[{"name":"Koltzov Institute of Developmental Biology of Russian Academy of Sciences, Moscow 119334, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,2,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s13287-022-03054-0","article-title":"Clinical application of mesenchymal stem cell in regenerative medicine: A narrative review","volume":"13","author":"Margiana","year":"2022","journal-title":"Stem Cell Res. Ther."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Weiss, A.R.R., and Dahlke, M.H. (2019). Immunomodulation by Mesenchymal Stem Cells (MSCs): Mechanisms of action of living, apoptotic, and dead MSCs. Front. Immunol., 10.","DOI":"10.3389\/fimmu.2019.01191"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"2287","DOI":"10.1634\/stemcells.2007-1122","article-title":"In search of the in vivo identity of mesenchymal stem cells","volume":"26","author":"Caplan","year":"2008","journal-title":"Stem Cells"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2094","DOI":"10.1111\/j.1582-4934.2011.01509.x","article-title":"Immunogenicity of allogeneic mesenchymal stem cells","volume":"16","author":"Schu","year":"2012","journal-title":"J. Cell. Mol. Med."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1186\/1478-811X-9-12","article-title":"Different populations and sources of human mesenchymal stem cells (MSC): A comparison of adult and neonatal tissue-derived MSC","volume":"9","author":"Hass","year":"2011","journal-title":"Cell Commun. Signal."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1007\/s00441-017-2699-4","article-title":"Comparative analysis of human Wharton\u2019s jelly mesenchymal stem cells derived from different parts of the same umbilical cord","volume":"372","author":"Bharti","year":"2018","journal-title":"Cell Tissue Res."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"646","DOI":"10.1634\/stemcells.2006-0208","article-title":"Human first-trimester fetal MSC express pluripotency markers and grow faster and have longer telomeres than adult MSC","volume":"25","author":"Guillot","year":"2007","journal-title":"Stem Cells"},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Zhuang, W.Z., Lin, Y.H., Su, L.J., Wu, M.S., Jeng, H.Y., Chang, H.C., Huang, Y.H., and Ling, T.Y. (2021). Mesenchymal stem\/stromal cell-based therapy: Mechanism, systemic safety and biodistribution for precision clinical applications. J. Biomed. Sci., 28.","DOI":"10.1186\/s12929-021-00725-7"},{"key":"ref_9","first-page":"5","article-title":"Characteristics and clinical applications of Wharton\u2019s jelly-derived mesenchymal stromal cells","volume":"68","author":"Liau","year":"2020","journal-title":"Curr. Res. Transl. Med."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"571","DOI":"10.1186\/s13287-021-02637-7","article-title":"Development of a human umbilical cord-derived mesenchymal stromal cell-based advanced therapy medicinal product to treat immune and\/or inflammatory diseases","volume":"12","author":"Mebarki","year":"2021","journal-title":"Stem Cell Res. Ther."},{"key":"ref_11","first-page":"901","article-title":"Umbilical cord mesenchymal stem cell (UC-MSC) transplantations for cerebral palsy","volume":"10","author":"Dong","year":"2018","journal-title":"Am. J. Transl. Res."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"384","DOI":"10.1186\/s13287-021-02451-1","article-title":"Application of mesenchymal stem cell sheet to treatment of ischemic heart disease","volume":"12","author":"Chang","year":"2021","journal-title":"Stem Cell Res. Ther."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"565","DOI":"10.21037\/atm.2020.03.218","article-title":"The clinical application of mesenchymal stem cells in liver disease: The current situation and potential future","volume":"8","author":"Zhang","year":"2020","journal-title":"Ann. Transl. Med."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Rota, C., Morigi, M., and Imberti, B. (2019). Stem Cell Therapies in Kidney Diseases: Progress and Challenges. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20112790"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"e00064-21","DOI":"10.1128\/CMR.00064-21","article-title":"Mesenchymal Stromal Cells: An Antimicrobial and Host-Directed Therapy for Complex Infectious Diseases","volume":"34","author":"Shaw","year":"2021","journal-title":"Clin. Microbiol. Rev."},{"key":"ref_16","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."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"778","DOI":"10.1136\/thorax-2023-220819","article-title":"Human mesenchymal stromal cells inhibit Mycobacterium avium replication in clinically relevant models of lung infection","volume":"79","author":"Shaw","year":"2024","journal-title":"Thorax"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"e202","DOI":"10.1097\/CCM.0000000000002073","article-title":"Cryopreserved, Xeno-Free Human Umbilical Cord Mesenchymal Stromal Cells Reduce Lung Injury Severity and Bacterial Burden in Rodent Escherichia coli-Induced Acute Respiratory Distress Syndrome","volume":"45","author":"Curley","year":"2017","journal-title":"Crit. Care Med."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Yang, H., Xu, F., Zheng, X., Yang, S., Ren, Z., and Yang, J. (2022). Human Umbilical Cord Mesenchymal Stem Cells Prevent Bacterial Biofilm Formation. BioMed Res. Int., 2022.","DOI":"10.1155\/2022\/1530525"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1177\/1753425919883932","article-title":"Human umbilical-cord mesenchymal stem cells inhibit bacterial growth and alleviate antibiotic resistance in neonatal imipenem-resistant Pseudomonas aeruginosa infection","volume":"26","author":"Ren","year":"2020","journal-title":"Innate Immun."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"E21429","DOI":"10.1097\/MD.0000000000021429","article-title":"Clinical remission of a critically ill COVID-19 patient treated by human umbilical cord mesenchymal stem cells: A case report","volume":"99","author":"Liang","year":"2020","journal-title":"Medicine"},{"key":"ref_22","first-page":"27","article-title":"Increased internalization of Staphylococcus aureus and cytokine expression in human Wharton\u2019s jelly mesenchymal stem cells","volume":"24","author":"Josse","year":"2014","journal-title":"Biomed. Mater. Eng."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1231","DOI":"10.1038\/s41467-022-28188-w","article-title":"Rapid expansion and extinction of antibiotic resistance mutations during treatment of acute bacterial respiratory infections","volume":"13","author":"Chung","year":"2022","journal-title":"Nat. Commun."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Sfeir, M.M. (2021). Diagnosis of Multidrug-Resistant Pathogens of Pneumonia. Diagnostics, 11.","DOI":"10.3390\/diagnostics11122287"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1186\/s40780-024-00367-5","article-title":"Antibiotic therapy for bacterial pneumonia","volume":"10","author":"Kato","year":"2024","journal-title":"J. Pharm. Heal. Care Sci."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"158","DOI":"10.1016\/j.tim.2021.05.005","article-title":"Towards efficient immunotherapy for bacterial infection","volume":"30","author":"McCulloch","year":"2021","journal-title":"Trends Microbiol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2331","DOI":"10.1002\/stem.2695","article-title":"Concise Review: Mesenchymal Stromal\/Stem Cells: A New Treatment for Sepsis and Septic Shock?","volume":"35","author":"Laroye","year":"2017","journal-title":"Stem Cells"},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Moeinabadi-Bidgoli, K., Rezaee, M., Rismanchi, H., Mohammadi, M.M., and Babajani, A. (2022). Mesenchymal Stem Cell-Derived Antimicrobial Peptides as Potential Anti-Neoplastic Agents: New Insight into Anticancer Mechanisms of Stem Cells and Exosomes. Front. Cell Dev. Biol., 10.","DOI":"10.3389\/fcell.2022.900418"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"2229","DOI":"10.1002\/stem.544","article-title":"Antibacterial effect of human mesenchymal stem cells is mediated in part from secretion of the antimicrobial peptide LL-37","volume":"28","author":"Krasnodembskaya","year":"2010","journal-title":"Stem Cells"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"2229","DOI":"10.1007\/s11259-023-10098-x","article-title":"Canine umbilical cord tissue derived mesenchymal stem cells naturally express mRNAs of some antimicrobial peptides","volume":"47","author":"Manna","year":"2023","journal-title":"Vet. Res. Commun."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"140","DOI":"10.1089\/jamp.2019.1542","article-title":"Nebulized Mesenchymal Stem Cell Derived Conditioned Medium Retains Antibacterial Properties Against Clinical Pathogen Isolates","volume":"33","author":"McCarthy","year":"2020","journal-title":"J. Aerosol Med. Pulm. Drug Deliv."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"114","DOI":"10.1093\/stcltm\/szab020","article-title":"Human Mesenchymal Stem\/Stromal Cells in Immune Regulation and Therapy","volume":"11","author":"Mezey","year":"2022","journal-title":"Stem Cells Transl. Med."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1186\/s13054-022-04287-4","article-title":"The safety and efficacy of mesenchymal stromal cells in ARDS: A meta-analysis of randomized controlled trials","volume":"27","author":"Wang","year":"2023","journal-title":"Crit. Care"},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Byrnes, D., Masterson, C., Brady, J., Horie, S., McCarthy, S.D., Gonzalez, H., O\u2019Toole, D., and Laffey, J. (2023). Delayed MSC therapy enhances resolution of organized pneumonia induced by antibiotic resistant Klebsiella pneumoniae infection. Front. Med., 10.","DOI":"10.3389\/fmed.2023.1132749"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"346","DOI":"10.1093\/stcltm\/szae003","article-title":"Efficacy and Safety of Umbilical Cord-Derived Mesenchymal Stromal Cell Therapy in Preclinical Models of Sepsis: A Systematic Review and Meta-analysis","volume":"13","author":"Hum","year":"2024","journal-title":"Stem Cells Transl. Med."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1186\/s13287-023-03295-7","article-title":"Research progress of engineered mesenchymal stem cells and their derived exosomes and their application in autoimmune\/inflammatory diseases","volume":"14","author":"Zhu","year":"2023","journal-title":"Stem Cell Res. Ther."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1093\/cei\/uxac016","article-title":"Genetically engineered mesenchymal stromal cells as a new trend for treatment of severe acute graft-versus-host disease","volume":"208","author":"Shahbaz","year":"2022","journal-title":"Clin. Exp. Immunol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"3369","DOI":"10.1002\/jgm.3369","article-title":"VEGF165 gene-modified human umbilical cord blood mesenchymal stem cells protect against acute liver failure in rats","volume":"23","author":"Chen","year":"2021","journal-title":"J. Gene Med."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"812","DOI":"10.1007\/s12015-020-10000-1","article-title":"Genetically Modified Mesenchymal Stromal\/Stem Cells: Application in Critical Illness","volume":"16","author":"Varkouhi","year":"2020","journal-title":"Stem Cell Rev. Rep."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1038\/s41531-022-00440-6","article-title":"Genetically engineered mesenchymal stem cells with dopamine synthesis for Parkinson\u2019s disease in animal models","volume":"8","author":"Li","year":"2022","journal-title":"NPJ Park. Dis."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"e10233","DOI":"10.15252\/emmm.201810233","article-title":"Genetically engineered distal airway stem cell transplantation protects mice from pulmonary infection","volume":"12","author":"Zhou","year":"2020","journal-title":"EMBO Mol. Med."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Shahror, R.A., Wu, C.C., Chiang, Y.H., and Chen, K.Y. (2020). Genetically Modified Mesenchymal Stem Cells: The Next Generation of Stem Cell-Based Therapy for TBI. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21114051"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1806","DOI":"10.1016\/j.ymthe.2020.05.014","article-title":"Antibacterial Fusion Protein BPI21\/LL-37 Modification Enhances the Therapeutic Efficacy of hUC-MSCs in Sepsis","volume":"28","author":"Li","year":"2020","journal-title":"Mol. Ther."},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Chen, C.H., and Lu, T.K. (2020). Development and Challenges of Antimicrobial Peptides for Therapeutic Applications. Antibiotics, 9.","DOI":"10.3390\/antibiotics9010024"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1664","DOI":"10.1128\/IAI.68.3.1664-1671.2000","article-title":"Bacterial Phosphorylcholine Decreases Susceptibility to the Antimicrobial Peptide LL-37\/hCAP18 Expressed in the Upper Respiratory Tract","volume":"68","author":"Lysenko","year":"2000","journal-title":"Infect. Immun."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"2243","DOI":"10.1007\/s00018-011-0716-4","article-title":"Bacterial resistance mechanisms against host defense peptides","volume":"68","author":"Koprivnjak","year":"2011","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Ridyard, K.E., and Overhage, J. (2021). The potential of human peptide ll-37 as an antimicrobial and anti-biofilm agent. Antibiotics, 10.","DOI":"10.3390\/antibiotics10060650"},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Takahashi, T., Kulkarni, N.N., Lee, E.Y., Zhang, L.J., Wong, G.C.L., and Gallo, R.L. (2018). Cathelicidin promotes inflammation by enabling binding of self-RNA to cell surface scavenger receptors. Sci. Rep., 8.","DOI":"10.1038\/s41598-018-22409-3"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1186\/s12934-021-01635-x","article-title":"Design and heterologous expression of a novel dimeric LL37 variant in Pichia pastoris","volume":"20","author":"Zhan","year":"2021","journal-title":"Microb. Cell Fact."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"428","DOI":"10.1016\/j.ejmech.2017.05.028","article-title":"LL-37-derived short antimicrobial peptide KR-12-a5 and its d-amino acid substituted analogs with cell selectivity, anti-biofilm activity, synergistic effect with conventional antibiotics, and anti-inflammatory activity","volume":"136","author":"Kim","year":"2017","journal-title":"Eur. J. Med. Chem."},{"key":"ref_51","doi-asserted-by":"crossref","unstructured":"Gasanov, V., Vorotelyak, E., and Vasiliev, A. (2024). Expression of the Antimicrobial Peptide SE-33-A2P, a Modified Analog of Cathelicidin, and an Analysis of Its Properties. Antibiotics, 13.","DOI":"10.3390\/antibiotics13020190"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"S148","DOI":"10.1134\/S1062359022140187","article-title":"Production of Antimicrobial Peptides (Cathelicidin Analogues) and Evaluation of Their Biological Properties","volume":"49","author":"Gasanov","year":"2022","journal-title":"Biol. Bull."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"252","DOI":"10.1134\/S1068162019020158","article-title":"Synthesis and Antimicrobial Activity of a New Drug Based on Retro-Analog Cathelicidin-Polypeptide SE-33","volume":"45","author":"Trenin","year":"2019","journal-title":"Russ. J. Bioorganic Chem."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1656","DOI":"10.1016\/j.transproceed.2017.03.078","article-title":"Thromboembolism Induced by Umbilical Cord Mesenchymal Stem Cell Infusion: A Report of Two Cases and Literature Review","volume":"49","author":"Wu","year":"2017","journal-title":"Transplant. Proc."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1093\/stmcls\/sxad087","article-title":"Procoagulant Properties of Mesenchymal Stem Cells and Extracellular Vesicles: A Novel Aspect of Thrombosis Pathogenesis","volume":"42","author":"Yang","year":"2024","journal-title":"Stem Cells"},{"key":"ref_56","unstructured":"National Research Council (US) Committee (2011). Guide for the Care and Use of Laboratory Animals, National Academies Press (US)."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"857","DOI":"10.1080\/17425255.2023.2279243","article-title":"A repeat-dose toxicity study of human umbilical cord mesenchymal stem cells in NOG mice by intravenous injection","volume":"19","author":"Shao","year":"2023","journal-title":"Expert Opin. Drug Metab. Toxicol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"469","DOI":"10.4049\/jimmunol.85.5.469","article-title":"Anaphylactogenic Properties of Soluble Antigen-Antibody Complexes in the Guinea Pig and Rabbit","volume":"85","author":"Weigle","year":"1960","journal-title":"J. Immunol."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"1241","DOI":"10.1111\/j.1348-0421.1984.tb00781.x","article-title":"The presence of anti-sheep red blood cell heterophile antibodies and their characteristics in murine schistosomiasis japonica","volume":"28","author":"Asahi","year":"1984","journal-title":"Microbiol. Immunol."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1186\/s13287-024-03781-6","article-title":"Effects of Staphylococcus aureus on stem cells and potential targeted treatment of inflammatory disorders","volume":"15","author":"Liu","year":"2024","journal-title":"Stem Cell Res. Ther."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"5303048","DOI":"10.1155\/2016\/5303048","article-title":"Antimicrobial Properties of Mesenchymal Stem Cells: Therapeutic Potential for Cystic Fibrosis Infection, and Treatment","volume":"2016","author":"Sutton","year":"2016","journal-title":"Stem Cells Int."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"1947","DOI":"10.1002\/stem.2337","article-title":"Protective Role of Adipose-Derived Stem Cells in Staphylococcus aureus-Induced Lung Injury is Mediated by RegIII\u03b3 Secretion","volume":"34","author":"Qian","year":"2016","journal-title":"Stem Cells"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1038\/s41392-022-01124-6","article-title":"Mesenchymal stromal cells alleviate acute respiratory distress syndrome through the cholinergic anti-inflammatory pathway","volume":"7","author":"Zhang","year":"2022","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"4045","DOI":"10.3390\/cimb44090277","article-title":"Toxicity, Safety, and Efficacy Studies on Mesenchymal Stem Cells Derived from Decidua basalis in Wistar Albino Rats by Intravenous and Subcutaneous Routes","volume":"44","author":"Subramani","year":"2022","journal-title":"Curr. Issues Mol. Biol."},{"key":"ref_65","doi-asserted-by":"crossref","unstructured":"Pichardo, A.H., Amadeo, F., Wilm, B., L\u00e9vy, R., Ressel, L., Murray, P., and S\u00e9e, V. (2022). Optical Tissue Clearing to Study the Intra-Pulmonary Biodistribution of Intravenously Delivered Mesenchymal Stromal Cells and Their Interactions with Host Lung Cells. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms232214171"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1016\/j.reth.2024.01.003","article-title":"Dynamic tracking of human umbilical cord mesenchymal stem cells (hUC-MSCs) following intravenous administration in mice model","volume":"25","author":"Chin","year":"2024","journal-title":"Regen. Ther."},{"key":"ref_67","doi-asserted-by":"crossref","unstructured":"Sadeghi, B., Moretti, G., Arnberg, F., Sam\u00e9n, E., Kohein, B., Catar, R., Kamhieh-Milz, J., Geissler, S., Moll, G., and Holmin, S. (2019). Preclinical Toxicity Evaluation of Clinical Grade Placenta-Derived Decidua Stromal Cells. Front. Immunol., 10.","DOI":"10.3389\/fimmu.2019.02685"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"1401","DOI":"10.1089\/scd.2011.0441","article-title":"A toxicity study of multiple-administration human umbilical cord mesenchymal stem cells in cynomolgus monkeys","volume":"21","author":"Wang","year":"2012","journal-title":"Stem Cells Dev."},{"key":"ref_69","doi-asserted-by":"crossref","unstructured":"Pan, W., Gu, L., Yang, H., Xu, C., Yang, Z., Lu, Q., Shi, Y., Zhang, L., Shao, J., and Chen, Y. (2023). Repeat-dose toxicity study of human umbilical cord mesenchymal stem cells in cynomolgus monkeys by intravenous and subcutaneous injection. Front. Cell Dev. Biol., 11.","DOI":"10.3389\/fcell.2023.1273723"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1186\/s13287-024-03647-x","article-title":"Amelioration of diabetic nephropathy in mice by a single intravenous injection of human mesenchymal stromal cells at early and later disease stages is associated with restoration of autophagy","volume":"15","author":"He","year":"2024","journal-title":"Stem Cell Res. Ther."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"111134","DOI":"10.1016\/j.intimp.2023.111134","article-title":"Human umbilical cord mesenchymal stem cells inhibit liver fibrosis via the microRNA-148a-5p\/SLIT3 axis","volume":"125","author":"Yuan","year":"2023","journal-title":"Int. Immunopharmacol."},{"key":"ref_72","doi-asserted-by":"crossref","unstructured":"Shi, X., Zhang, K., Qi, Q., Zhou, W., Yu, F., and Zhang, Y. (2024). Human umbilical cord-derived mesenchymal stem cells attenuate hepatic stellate cells activation and liver fibrosis. Mol. Biol. Rep., 51.","DOI":"10.1007\/s11033-024-09664-6"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1186\/scrt489","article-title":"Mesenchymal stem cells, not conditioned medium, contribute to kidney repair after ischemia-reperfusion injury","volume":"5","author":"Xing","year":"2014","journal-title":"Stem Cell Res. Ther."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"1402","DOI":"10.1002\/eji.201444988","article-title":"Antimicrobial peptide LL-37 promotes antigen-specific immune responses in mice by enhancing Th17-skewed mucosal and systemic immunities","volume":"45","author":"Kim","year":"2015","journal-title":"Eur. J. Immunol."},{"key":"ref_75","doi-asserted-by":"crossref","unstructured":"Marquina, M., Collado, J.A., P\u00e9rez-Cruz, M., Fern\u00e1ndez-Pernas, P., Fafi\u00e1n-Labora, J., Blanco, F.J., M\u00e1\u00f1ez, R., Arufe, M.C., and Costa, C. (2017). Biodistribution and immunogenicity of allogeneic mesenchymal stem cells in a rat model of intraarticular chondrocyte xenotransplantation. Front. Immunol., 8.","DOI":"10.3389\/fimmu.2017.01465"},{"key":"ref_76","doi-asserted-by":"crossref","unstructured":"Zhang, L., Wei, X., Zhang, R., Koci, M., Si, D., Ahmad, B., Cheng, J., and Wang, J. (2019). Development of a Highly Efficient Hybrid Peptide That Increases Immunomodulatory Activity Via the TLR4-Mediated Nuclear Factor-\u03baB Signaling Pathway. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20246161"},{"key":"ref_77","doi-asserted-by":"crossref","unstructured":"Franquesa, M., Hoogduijn, M.J., Bestard, O., and Griny\u00f3, J.M. (2012). Immunomodulatory effect of mesenchymal stem cells on B cells. Front. Immunol., 3.","DOI":"10.3389\/fimmu.2012.00212"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"140","DOI":"10.1097\/ALN.0000000000003018","article-title":"Human Umbilical Cord Mesenchymal Stromal Cells Attenuate Systemic Sepsis in Part by Enhancing Peritoneal Macrophage Bacterial Killing Via Heme Oxygenase-1 Induction in Rats","volume":"132","author":"Jerkic","year":"2020","journal-title":"Anesthesiology"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"971","DOI":"10.1189\/jlb.0513304","article-title":"Antimicrobial peptide LL-37 promotes bacterial phagocytosis by human macrophages","volume":"95","author":"Wan","year":"2014","journal-title":"J. Leukoc. Biol."},{"key":"ref_80","doi-asserted-by":"crossref","unstructured":"Lu, D., Xu, Y., Liu, Q., and Zhang, Q. (2021). Mesenchymal Stem Cell-Macrophage Crosstalk and Maintenance of Inflammatory Microenvironment Homeostasis. Front. Cell Dev. Biol., 9.","DOI":"10.3389\/fcell.2021.681171"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"78","DOI":"10.1177\/1074248412453875","article-title":"Human macrophage regulation via interaction with cardiac adipose tissue-derived mesenchymal stromal cells","volume":"18","author":"Asher","year":"2013","journal-title":"J. Cardiovasc. Pharmacol. Ther."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1186\/s12967-016-0792-1","article-title":"Mesenchymal stem cells and their secreted molecules predominantly ameliorate fulminant hepatic failure and chronic liver fibrosis in mice respectively","volume":"14","author":"Huang","year":"2016","journal-title":"J. Transl. Med."},{"key":"ref_83","doi-asserted-by":"crossref","unstructured":"Fan, L., Hu, C., Chen, J., Cen, P., Wang, J., and Li, L. (2016). Interaction between Mesenchymal Stem Cells and B-Cells. Int. J. Mol. Sci., 17.","DOI":"10.3390\/ijms17050650"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"9824698","DOI":"10.1155\/2017\/9824698","article-title":"In Vivo Immunogenic Response to Allogeneic Mesenchymal Stem Cells and the Role of Preactivated Mesenchymal Stem Cells Cotransplanted with Allogeneic Islets","volume":"2017","author":"Oliveira","year":"2017","journal-title":"Stem Cells Int."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1038\/s41392-022-00932-0","article-title":"The secretion profile of mesenchymal stem cells and potential applications in treating human diseases","volume":"7","author":"Han","year":"2022","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1007\/5584_2017_118","article-title":"Contrasting Views on the Role of Mesenchymal Stromal\/Stem Cells in Tumour Growth: A Systematic Review of Experimental Design","volume":"1083","author":"Oloyo","year":"2018","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"152","DOI":"10.1186\/s13287-021-02222-y","article-title":"Human umbilical cord-derived mesenchymal stem\/stromal cells: A promising candidate for the development of advanced therapy medicinal products","volume":"12","author":"Mebarki","year":"2021","journal-title":"Stem Cell Res. Ther."},{"key":"ref_88","doi-asserted-by":"crossref","unstructured":"Drobiova, H., Sindhu, S., Ahmad, R., Haddad, D., Al-Mulla, F., and Al Madhoun, A. (2023). Wharton\u2019s jelly mesenchymal stem cells: A concise review of their secretome and prospective clinical applications. Front. Cell Dev. Biol., 11.","DOI":"10.3389\/fcell.2023.1211217"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"983","DOI":"10.1016\/j.bbrc.2014.03.051","article-title":"Low immunogenicity of allogeneic human umbilical cord blood-derived mesenchymal stem cells in vitro and in vivo","volume":"446","author":"Lee","year":"2014","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_90","doi-asserted-by":"crossref","unstructured":"Moroncini, G., Paolini, C., Orlando, F., Capelli, C., Grieco, A., Tonnini, C., Agarbati, S., Mondini, E., Saccomanno, S., and Goteri, G. (2018). Mesenchymal stromal cells from human umbilical cord prevent the development of lung fibrosis in immunocompetent mice. PLoS ONE, 13.","DOI":"10.1371\/journal.pone.0196048"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1186\/s13756-023-01210-6","article-title":"The global prevalence of methicillin-resistant Staphylococcus aureus colonization in residents of elderly care centers: A systematic review and meta-analysis","volume":"12","author":"Hasanpour","year":"2023","journal-title":"Antimicrob. Resist. Infect. Control"},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"1451","DOI":"10.1161\/CIRCULATIONAHA.105.537480","article-title":"Dynamic Imaging of Allogeneic Mesenchymal Stem Cells Trafficking to Myocardial Infarction","volume":"112","author":"Kraitchman","year":"2005","journal-title":"Circulation"},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1124\/jpet.121.000607","article-title":"Define Mesenchymal Stem Cell from Its Fate: Biodisposition of Human Mesenchymal Stem Cells in Normal and Concanavalin A-Induced Liver Injury Mice","volume":"379","author":"Han","year":"2021","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"37","DOI":"10.62347\/JAWM2040","article-title":"Mesenchymal stromal cell-based therapy in lung diseases; from research to clinic","volume":"13","author":"Yuan","year":"2024","journal-title":"Am. J. Stem Cells"},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"533","DOI":"10.1136\/thoraxjnl-2011-201176","article-title":"Mesenchymal stem cells enhance survival and bacterial clearance in murine Escherichia coli pneumonia","volume":"67","author":"Gupta","year":"2012","journal-title":"Thorax"},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"1047","DOI":"10.1164\/rccm.201001-0010OC","article-title":"Mesenchymal stem cells reduce inflammation while enhancing bacterial clearance and improving survival in sepsis","volume":"182","author":"Mei","year":"2010","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"S54","DOI":"10.1513\/AnnalsATS.201406-254MG","article-title":"Therapeutic potential of mesenchymal stromal cells for acute respiratory distress syndrome","volume":"12","author":"Matthay","year":"2015","journal-title":"Ann. Am. Thorac. Soc."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"913","DOI":"10.1002\/stem.643","article-title":"Concise review: Mesenchymal stem cells for acute lung injury: Role of paracrine soluble factors","volume":"29","author":"Lee","year":"2011","journal-title":"Stem Cells"},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"4236973","DOI":"10.1155\/2019\/4236973","article-title":"Mesenchymal Stem Cell-Based Therapy of Inflammatory Lung Diseases: Current Understanding and Future Perspectives","volume":"2019","author":"Harrell","year":"2019","journal-title":"Stem Cells Int."},{"key":"ref_100","doi-asserted-by":"crossref","unstructured":"Nagaoka, I., Tamura, H., and Reich, J. (2020). Therapeutic Potential of Cathelicidin Peptide LL-37, an Antimicrobial Agent, in a Murine Sepsis Model. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21175973"},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"565","DOI":"10.1177\/1753425920936754","article-title":"Antimicrobial peptide LL-37 ameliorates a murine sepsis model via the induction of microvesicle release from neutrophils","volume":"26","author":"Kumagai","year":"2020","journal-title":"Innate Immun."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"111580","DOI":"10.1016\/j.intimp.2024.111580","article-title":"LL-37 improves sepsis-induced acute lung injury by suppressing pyroptosis in alveolar epithelial cells","volume":"129","author":"Wang","year":"2024","journal-title":"Int. Immunopharmacol."}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/14\/5\/341\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T16:43:19Z","timestamp":1760028199000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/14\/5\/341"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,2,26]]},"references-count":102,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2025,3]]}},"alternative-id":["cells14050341"],"URL":"https:\/\/doi.org\/10.3390\/cells14050341","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,2,26]]}}}