PMID- 35307492 OWN - NLM STAT- MEDLINE DCOM- 20220525 LR - 20220613 IS - 1873-1708 (Electronic) IS - 0890-6238 (Linking) VI - 110 DP - 2022 Jun TI - Toxicity from a single injection of human umbilical cord mesenchymal stem cells into rat ovaries. PG - 9-18 LID - S0890-6238(22)00032-6 [pii] LID - 10.1016/j.reprotox.2022.03.006 [doi] AB - Intraovarian injection of human umbilical cord mesenchymal stem cells (hUC-MSCs) has been applied and with promising therapeutic effects, but its toxicity and safety remain uncertain. This study evaluated the toxic effects and the affected target organs after a single injection of hUC-MSCs into bilateral rat ovaries. Sixty Sprague-Dawley rats were randomly divided into four groups and intraovarian injected with three different doses of hUC-MSC suspension. Toxicity-related manifestations occurred over the following 14 days postinjection. On day (D)5 and D15, we assessed the clinical pathology; immunotoxicity, including the cytokine IFN-gamma, TNF-alpha, IL-4, and IL-6 levels; the immune organs, and the organ weights. On D5, inflammatory cells mainly infiltrated the ovaries of the low- and medium-dose groups, whereas inflammatory cells infiltrated the oviduct in the medium- and high-dose groups. On D15, inflammatory cells infiltrated the corpus luteal cysts, ovarian sacs and oviducts in each group. Body weights; organ weights; immunotoxicity; clinical pathology and histopathological examinations of the immune organs did not significantly differ among the groups. No obvious hUC-MSC-related clinical symptoms were observed except in the rats that died. The high-dose group exhibited significantly higher mortality than did the control and low-dose groups. Deaths in the high-dose group, who received approximately 50 times the standard clinical dose, were related to the intraovarian hUC-MSC injection. The maximum tolerated dose was approximately ten times the standard clinical dose. The ovary and oviduct may be the target organs for this toxicity. This report provides dosage references and guidance for clinical applications of intraovarian hUC-MSC injections. CI - Copyright (c) 2022. Published by Elsevier Inc. FAU - Shi, Libing AU - Shi L AD - Assisted Reproduction Unit, Department of Obstetrics and Gynecology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Key Laboratory of Reproductive Dysfunction Management of Zhejiang Province, Hangzhou 310016, PR China. FAU - Zhang, Yingyi AU - Zhang Y AD - Assisted Reproduction Unit, Department of Obstetrics and Gynecology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Key Laboratory of Reproductive Dysfunction Management of Zhejiang Province, Hangzhou 310016, PR China. FAU - Dong, Xinwei AU - Dong X AD - Center for Drug Safety Evaluation and Research of Zhejiang University, Hangzhou 310016, PR China. FAU - Pan, Yibin AU - Pan Y AD - Assisted Reproduction Unit, Department of Obstetrics and Gynecology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Key Laboratory of Reproductive Dysfunction Management of Zhejiang Province, Hangzhou 310016, PR China. FAU - Ying, Hanqi AU - Ying H AD - Assisted Reproduction Unit, Department of Obstetrics and Gynecology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Key Laboratory of Reproductive Dysfunction Management of Zhejiang Province, Hangzhou 310016, PR China. FAU - Chen, Jianmin AU - Chen J AD - Assisted Reproduction Unit, Department of Obstetrics and Gynecology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Key Laboratory of Reproductive Dysfunction Management of Zhejiang Province, Hangzhou 310016, PR China. FAU - Yang, Weijie AU - Yang W AD - Assisted Reproduction Unit, Department of Obstetrics and Gynecology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Key Laboratory of Reproductive Dysfunction Management of Zhejiang Province, Hangzhou 310016, PR China. FAU - Zhang, Yi AU - Zhang Y AD - Assisted Reproduction Unit, Department of Obstetrics and Gynecology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Key Laboratory of Reproductive Dysfunction Management of Zhejiang Province, Hangzhou 310016, PR China. FAU - Fei, Haiyi AU - Fei H AD - Assisted Reproduction Unit, Department of Obstetrics and Gynecology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Key Laboratory of Reproductive Dysfunction Management of Zhejiang Province, Hangzhou 310016, PR China. FAU - Liu, Xiu AU - Liu X AD - Assisted Reproduction Unit, Department of Obstetrics and Gynecology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Key Laboratory of Reproductive Dysfunction Management of Zhejiang Province, Hangzhou 310016, PR China. FAU - Wei, Cheng AU - Wei C AD - Assisted Reproduction Unit, Department of Obstetrics and Gynecology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Key Laboratory of Reproductive Dysfunction Management of Zhejiang Province, Hangzhou 310016, PR China. FAU - Lin, Huizhen AU - Lin H AD - Assisted Reproduction Unit, Department of Obstetrics and Gynecology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Key Laboratory of Reproductive Dysfunction Management of Zhejiang Province, Hangzhou 310016, PR China. FAU - Zhou, Hanjing AU - Zhou H AD - Assisted Reproduction Unit, Department of Obstetrics and Gynecology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Key Laboratory of Reproductive Dysfunction Management of Zhejiang Province, Hangzhou 310016, PR China. FAU - Zhao, Chenqiong AU - Zhao C AD - Assisted Reproduction Unit, Department of Obstetrics and Gynecology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Key Laboratory of Reproductive Dysfunction Management of Zhejiang Province, Hangzhou 310016, PR China. FAU - Yang, Anran AU - Yang A AD - Assisted Reproduction Unit, Department of Obstetrics and Gynecology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Key Laboratory of Reproductive Dysfunction Management of Zhejiang Province, Hangzhou 310016, PR China. FAU - Zhou, Feng AU - Zhou F AD - Assisted Reproduction Unit, Department of Obstetrics and Gynecology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Key Laboratory of Reproductive Dysfunction Management of Zhejiang Province, Hangzhou 310016, PR China. Electronic address: zhoufeng82@zju.edu.cn. FAU - Zhang, Songying AU - Zhang S AD - Assisted Reproduction Unit, Department of Obstetrics and Gynecology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Key Laboratory of Reproductive Dysfunction Management of Zhejiang Province, Hangzhou 310016, PR China. Electronic address: zhangsongying@zju.edu.cn. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20220317 PL - United States TA - Reprod Toxicol JT - Reproductive toxicology (Elmsford, N.Y.) JID - 8803591 SB - IM MH - Animals MH - Female MH - Humans MH - *Mesenchymal Stem Cell Transplantation MH - *Mesenchymal Stem Cells MH - Ovary MH - Rats MH - Rats, Sprague-Dawley MH - Umbilical Cord OTO - NOTNLM OT - Human umbilical cord mesenchymal stem cells OT - Intraovarian injection OT - Maximum tolerated dose OT - Premature ovarian insufficiency OT - Single-injection toxicity study OT - Sprague-Dawley rats EDAT- 2022/03/22 06:00 MHDA- 2022/05/26 06:00 CRDT- 2022/03/21 05:34 PHST- 2021/12/21 00:00 [received] PHST- 2022/02/26 00:00 [revised] PHST- 2022/03/14 00:00 [accepted] PHST- 2022/03/22 06:00 [pubmed] PHST- 2022/05/26 06:00 [medline] PHST- 2022/03/21 05:34 [entrez] AID - S0890-6238(22)00032-6 [pii] AID - 10.1016/j.reprotox.2022.03.006 [doi] PST - ppublish SO - Reprod Toxicol. 2022 Jun;110:9-18. doi: 10.1016/j.reprotox.2022.03.006. Epub 2022 Mar 17.