{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T16:06:33Z","timestamp":1790352393272,"version":"4.1.0"},"reference-count":39,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,10,25]],"date-time":"2023-10-25T00:00:00Z","timestamp":1698192000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cell Dev. Biol."],"abstract":"<jats:p>Human umbilical cord mesenchymal stem cells (hUC-MSCs) are proposed for the treatment of acute lung injury and atopic dermatitis. To advance hUC-MSC entry into clinical trials, the effects of hUC-MSCs on the general toxicity, immune perturbation and toxicokinetic study of hUC-MSCs in cynomolgus monkeys were assessed. hUC-MSCs were administered to cynomolgus monkeys by intravenous infusion of 3.0 \u00d7 10<jats:sup>6<\/jats:sup> or 3.0 \u00d7 10<jats:sup>7<\/jats:sup>cells\/kg or by subcutaneous injection of 3.0 \u00d7 10<jats:sup>7<\/jats:sup>cells\/kg twice a week for 3\u00a0weeks followed by withdrawal and observation for 6\u00a0weeks. Toxicity was assessed by clinical observation, clinical pathology, ophthalmology, immunotoxicology and histopathology. Moreover, toxicokinetic study was performed using a validated qPCR method after the first and last dose. After 3rd or 4th dosing, one or three the monkeys in the intravenous high-dose group exhibited transient coma, which was eliminated by slow-speed infusion after 5th or 6th dosing. In all dose groups, hUC-MSCs significantly increased NEUT levels and decreased LYMPH and CD3<jats:sup>+<\/jats:sup> levels, which are related to the immunosuppressive effect of hUC-MSCs. Subcutaneous nodules and granulomatous foci were found at the site of administration in all monkeys in the subcutaneous injection group. Other than above abnormalities, no obvious systemic toxicity was observed in any group. The hUC-MSCs was detectable in blood only within 1\u00a0h after intravenous and subcutaneous administration. The present study declared the preliminary safety of hUC-MSCs, but close monitoring of hUC-MSCs for adverse effects, such as coma induced by intravenous infusion, is warranted in future clinical trials.<\/jats:p>","DOI":"10.3389\/fcell.2023.1273723","type":"journal-article","created":{"date-parts":[[2023,10,25]],"date-time":"2023-10-25T10:20:11Z","timestamp":1698229211000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":12,"title":["Repeat-dose toxicity study of human umbilical cord mesenchymal stem cells in cynomolgus monkeys by intravenous and subcutaneous injection"],"prefix":"10.3389","volume":"11","author":[{"given":"Wei","family":"Pan","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liqiang","family":"Gu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongzhong","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cong","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhengbiao","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qijiong","family":"Lu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuhua","family":"Shi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lili","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinjin","family":"Shao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yunxiang","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Pan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Feifei","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruolang","family":"Pan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinfeng","family":"Liang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lijiang","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2023,10,25]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"454","DOI":"10.2174\/1574888x16999201124153000","article-title":"Applications of umbilical cord derived mesenchymal stem cells in autoimmune and immunological disorders: from literature to clinical practice","volume":"16","author":"Abbaspanah","year":"2021","journal-title":"Curr. Stem Cell Res. Ther."},{"key":"B2","doi-asserted-by":"publisher","first-page":"1192","DOI":"10.1161\/circresaha.117.310712","article-title":"Safety and efficacy of the intravenous infusion of umbilical cord mesenchymal stem cells in patients with heart failure: a phase 1\/2 randomized controlled trial (rimecard trial [randomized clinical trial of intravenous infusion umbilical cord mesenchymal stem cells on cardiopathy])","volume":"121","author":"Bartolucci","year":"2017","journal-title":"Circ. Res."},{"key":"B39","doi-asserted-by":"publisher","first-page":"155","DOI":"10.3389\/fneur.2015.00155","article-title":"The dark side of the force\u2014constraints and complications of cell therapies for stroke","volume":"6","author":"Boltze","year":"2015","journal-title":"Front. Neurol."},{"key":"B3","doi-asserted-by":"publisher","first-page":"12","DOI":"10.13041\/jpvm.2016.40.1.12","article-title":"Canine mesenchymal stem cells immunomodulate atopic dermatitis through the induction of regulatory T cells in an ex vivo experimental study","volume":"40","author":"Byeon","year":"2016","journal-title":"J. Prev. Veterinary Med."},{"key":"B4","unstructured":"Regulatory guidelines for non-clinical safety valuations studies2014"},{"key":"B5","doi-asserted-by":"publisher","first-page":"e110338","DOI":"10.1371\/journal.pone.0110338","article-title":"An increase in CD3+CD4+CD25+ regulatory T cells after administration of umbilical cord-derived mesenchymal stem cells during sepsis","volume":"9","author":"Chao","year":"2014","journal-title":"PLoS One"},{"key":"B6","doi-asserted-by":"publisher","first-page":"7301","DOI":"10.1002\/jcp.27488","article-title":"Mesenchymal stem cells overexpressing heme oxygenase-1 ameliorate lipopolysaccharide-induced acute lung injury in rats","volume":"234","author":"Chen","year":"2019","journal-title":"J. Cell Physiol."},{"key":"B7","doi-asserted-by":"publisher","first-page":"e1012","DOI":"10.1212\/wnl.0000000000011440","article-title":"Efficacy and safety of intravenous mesenchymal stem cells for ischemic stroke","volume":"96","author":"Chung","year":"2021","journal-title":"Neurology"},{"key":"B8","doi-asserted-by":"publisher","first-page":"2698","DOI":"10.3390\/ijms20112698","article-title":"Mesenchymal stem cells for spinal cord injury: current options, limitations, and future of cell therapy","volume":"20","author":"Cofano","year":"2019","journal-title":"Int. J. Mol. Sci."},{"key":"B9","doi-asserted-by":"publisher","first-page":"1021102","DOI":"10.3389\/fimmu.2022.1021102","article-title":"RNA-Sequencing approach for exploring the therapeutic effect of umbilical cord mesenchymal stem\/stromal cells on lipopolysaccharide-induced acute lung injury","volume":"13","author":"Cui","year":"2022","journal-title":"Front. Immunol."},{"key":"B10","doi-asserted-by":"publisher","first-page":"655","DOI":"10.3727\/096368910X536473","article-title":"Immunogenicity and immunomodulatory properties of umbilical cord lining mesenchymal stem cells","volume":"20","author":"Deuse","year":"2011","journal-title":"Cell Transpl."},{"key":"B11","doi-asserted-by":"publisher","first-page":"3838","DOI":"10.1182\/blood.v99.10.3838","article-title":"Human bone marrow stromal cells suppress T-lymphocyte proliferation induced by cellular or nonspecific mitogenic stimuli","volume":"99","author":"Di Nicola","year":"2002","journal-title":"Blood"},{"key":"B12","doi-asserted-by":"publisher","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":"B13","doi-asserted-by":"publisher","first-page":"886","DOI":"10.3390\/cells8080886","article-title":"Mesenchymal stem cells for regenerative medicine","volume":"8","author":"Han","year":"2019","journal-title":"Cells"},{"key":"B14","doi-asserted-by":"publisher","first-page":"891","DOI":"10.1159\/000481639","article-title":"Chronic toxicity test in cynomolgus monkeys for 98 Days with repeated intravenous infusion of cynomolgus umbilical cord mesenchymal stem cells","volume":"43","author":"He","year":"2017","journal-title":"Cell Physiol. Biochem."},{"key":"B15","doi-asserted-by":"publisher","first-page":"272","DOI":"10.1038\/s41392-022-01134-4","article-title":"Stem cell-based therapy for human diseases","volume":"7","author":"Hoang","year":"2022","journal-title":"Signal Transduct. Target. Ther."},{"key":"B16","doi-asserted-by":"publisher","first-page":"1293","DOI":"10.3349\/ymj.2013.54.5.1293","article-title":"Familial occurrence of pulmonary embolism after intravenous, adipose tissue-derived stem cell therapy","volume":"54","author":"Jung","year":"2013","journal-title":"Yonsei Med. J."},{"key":"B17","doi-asserted-by":"publisher","first-page":"248","DOI":"10.1002\/stem.2401","article-title":"Clinical trial of human umbilical cord blood-derived stem cells for the treatment of moderate-to-severe atopic dermatitis: phase I\/IIa studies","volume":"35","author":"Kim","year":"2017","journal-title":"Stem cells Dayt. Ohio)"},{"key":"B18","doi-asserted-by":"publisher","first-page":"1175","DOI":"10.3389\/fphar.2018.01175","article-title":"Human adipose tissue-derived mesenchymal stem cells attenuate atopic dermatitis by regulating the expression of MIP-2, miR-122a-SOCS1 Axis, and Th1\/Th2 responses","volume":"9","author":"Kim","year":"2018","journal-title":"Front. Pharmacol."},{"key":"B19","doi-asserted-by":"publisher","first-page":"1901647","DOI":"10.1183\/13993003.01647-2019","article-title":"2019 ESC Guidelines for the diagnosis and management of acute pulmonary embolism developed in collaboration with the European Respiratory Society (ERS): the Task Force for the diagnosis and management of acute pulmonary embolism of the European Society of Cardiology (ESC)","volume":"54","author":"Konstantinides","year":"2019","journal-title":"Eur. Respir. J."},{"key":"B20","doi-asserted-by":"publisher","first-page":"60","DOI":"10.1186\/s13287-020-1583-4","article-title":"Allogeneic umbilical cord-derived mesenchymal stem cell transplantation for treating chronic obstructive pulmonary disease: a pilot clinical study","volume":"11","author":"Le Thi Bich","year":"2020","journal-title":"Stem Cell Res. Ther."},{"key":"B21","doi-asserted-by":"publisher","first-page":"664","DOI":"10.11844\/cjcb.2020.04.0014","article-title":"Immunotoxicity and immunomodulatory effects of continuous intravenous infusion of human umbilical cord mesenchymal stem cells in cynomolgus monkeys","volume":"42","author":"Le","year":"2020","journal-title":"Chin. J. Cell Biol."},{"key":"B22","doi-asserted-by":"publisher","first-page":"816","DOI":"10.1182\/blood-2007-12-128702","article-title":"The CD34-like protein PODXL and alpha6-integrin (CD49f) identify early progenitor MSCs with increased clonogenicity and migration to infarcted heart in mice","volume":"113","author":"Lee","year":"2009","journal-title":"Blood"},{"key":"B23","doi-asserted-by":"publisher","first-page":"883996","DOI":"10.3389\/fcell.2022.883996","article-title":"Reproductive and developmental toxicity assessment of human umbilical cord mesenchymal stem cells in rats","volume":"10","author":"Li","year":"2022","journal-title":"Front. Cell Dev. Biol."},{"key":"B24","first-page":"1990","article-title":"Substance P-induced RAD16-I scaffold mediated hUCMSCs stereo-culture triggers production of mineralized nodules and collagen-like fibers by promoting osteogenic genes expression","volume":"13","author":"Li","year":"2021","journal-title":"Am. J. Transl. Res."},{"key":"B25","doi-asserted-by":"publisher","first-page":"12","DOI":"10.1186\/s10020-021-00272-9","article-title":"Long non-coding RNA CIR inhibits chondrogenic differentiation of mesenchymal stem cells by epigenetically suppressing ATOH8 via methyltransferase EZH2","volume":"27","author":"Liu","year":"2021","journal-title":"Mol. Med."},{"key":"B26","doi-asserted-by":"publisher","first-page":"e0187637","DOI":"10.1371\/journal.pone.0187637","article-title":"Hypoxia-preconditioned mesenchymal stem cells ameliorate ischemia\/reperfusion-induced lung injury","volume":"12","author":"Liu","year":"2017","journal-title":"PLoS One"},{"key":"B27","doi-asserted-by":"publisher","first-page":"S569","DOI":"10.1097\/CCM.0b013e3181f1ff1d","article-title":"Mesenchymal stem cells for acute lung injury: preclinical evidence","volume":"38","author":"Matthay","year":"2010","journal-title":"Crit. Care Med."},{"key":"B28","doi-asserted-by":"publisher","first-page":"3323","DOI":"10.1007\/s00018-019-03125-1","article-title":"Biological functions of mesenchymal stem cells and clinical implications","volume":"76","author":"Naji","year":"2019","journal-title":"Cell Mol. Life Sci."},{"key":"B29","unstructured":"Review report on the safety and efficacy of temcell for GVHD2015"},{"key":"B30","doi-asserted-by":"publisher","first-page":"7873625","DOI":"10.1155\/2018\/7873625","article-title":"Comparative effects of umbilical cord- and menstrual blood-derived MSCs in repairing acute lung injury","volume":"2018","author":"Ren","year":"2018","journal-title":"Stem Cells Int."},{"key":"B31","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1111\/j.1365-2249.2011.04327.x","article-title":"Immunomodulatory properties and therapeutic application of mesenchymal stem cells","volume":"164","author":"Shi","year":"2011","journal-title":"Clin. Exp. Immunol."},{"key":"B32","doi-asserted-by":"publisher","first-page":"653","DOI":"10.1016\/j.tips.2020.06.009","article-title":"Mesenchymal stem cell immunomodulation: mechanisms and therapeutic potential","volume":"41","author":"Song","year":"2020","journal-title":"Trends Pharmacol. Sci."},{"key":"B33","doi-asserted-by":"publisher","first-page":"203","DOI":"10.1016\/j.bbrc.2012.12.134","article-title":"Tissue factor triggers procoagulation in transplanted mesenchymal stem cells leading to thromboembolism","volume":"431","author":"Tatsumi","year":"2013","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"B34","doi-asserted-by":"publisher","first-page":"3057624","DOI":"10.1155\/2018\/3057624","article-title":"Mesenchymal stem cell-based immunomodulation: properties and clinical application","volume":"2018","author":"Wang","year":"2018","journal-title":"Stem Cells Int."},{"key":"B35","doi-asserted-by":"publisher","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":"B36","doi-asserted-by":"publisher","first-page":"1590","DOI":"10.1378\/chest.12-2094","article-title":"A placebo-controlled, randomized trial of mesenchymal stem cells in COPD","volume":"143","author":"Weiss","year":"2013","journal-title":"Chest"},{"key":"B37","doi-asserted-by":"publisher","first-page":"213","DOI":"10.1007\/s12272-012-0202-z","article-title":"Immunomodulatory properties of mesenchymal stem cells and their therapeutic applications","volume":"35","author":"Yi","year":"2012","journal-title":"Arch. Pharm. Res."},{"key":"B38","doi-asserted-by":"publisher","first-page":"293","DOI":"10.1016\/j.molimm.2017.03.003","article-title":"Immunomodulatory function of whole human umbilical cord derived mesenchymal stem cells","volume":"87","author":"Zhang","year":"2017","journal-title":"Mol. Immunol."}],"container-title":["Frontiers in Cell and Developmental Biology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcell.2023.1273723\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,10,25]],"date-time":"2023-10-25T10:20:15Z","timestamp":1698229215000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcell.2023.1273723\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,10,25]]},"references-count":39,"alternative-id":["10.3389\/fcell.2023.1273723"],"URL":"https:\/\/doi.org\/10.3389\/fcell.2023.1273723","relation":{},"ISSN":["2296-634X"],"issn-type":[{"value":"2296-634X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,10,25]]},"article-number":"1273723"}}