PMID- 38020919 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20231201 IS - 2296-634X (Print) IS - 2296-634X (Electronic) IS - 2296-634X (Linking) VI - 11 DP - 2023 TI - Repeat-dose toxicity study of human umbilical cord mesenchymal stem cells in cynomolgus monkeys by intravenous and subcutaneous injection. PG - 1273723 LID - 10.3389/fcell.2023.1273723 [doi] LID - 1273723 AB - 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 x 10(6) or 3.0 x 10(7)cells/kg or by subcutaneous injection of 3.0 x 10(7)cells/kg twice a week for 3 weeks followed by withdrawal and observation for 6 weeks. 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(+) 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 h 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. CI - Copyright (c) 2023 Pan, Gu, Yang, Xu, Yang, Lu, Shi, Zhang, Shao, Chen, Pan, Wu, Pan, Liang and Zhang. FAU - Pan, Wei AU - Pan W AD - Key Laboratory of Drug Safety Evaluation and Research of Zhejiang Province, Center of Safety Evaluation and Research, Hangzhou Medical College, Hangzhou, China. AD - Engineering Research Center of Novel Vaccine of Zhejiang Province, Hangzhou Medical College, Hangzhou, China. FAU - Gu, Liqiang AU - Gu L AD - Key Laboratory of Drug Safety Evaluation and Research of Zhejiang Province, Center of Safety Evaluation and Research, Hangzhou Medical College, Hangzhou, China. AD - Engineering Research Center of Novel Vaccine of Zhejiang Province, Hangzhou Medical College, Hangzhou, China. FAU - Yang, Hongzhong AU - Yang H AD - Key Laboratory of Drug Safety Evaluation and Research of Zhejiang Province, Center of Safety Evaluation and Research, Hangzhou Medical College, Hangzhou, China. AD - Engineering Research Center of Novel Vaccine of Zhejiang Province, Hangzhou Medical College, Hangzhou, China. FAU - Xu, Cong AU - Xu C AD - Key Laboratory of Drug Safety Evaluation and Research of Zhejiang Province, Center of Safety Evaluation and Research, Hangzhou Medical College, Hangzhou, China. AD - Engineering Research Center of Novel Vaccine of Zhejiang Province, Hangzhou Medical College, Hangzhou, China. FAU - Yang, Zhengbiao AU - Yang Z AD - Key Laboratory of Drug Safety Evaluation and Research of Zhejiang Province, Center of Safety Evaluation and Research, Hangzhou Medical College, Hangzhou, China. AD - Engineering Research Center of Novel Vaccine of Zhejiang Province, Hangzhou Medical College, Hangzhou, China. FAU - Lu, Qijiong AU - Lu Q AD - Key Laboratory of Drug Safety Evaluation and Research of Zhejiang Province, Center of Safety Evaluation and Research, Hangzhou Medical College, Hangzhou, China. AD - Engineering Research Center of Novel Vaccine of Zhejiang Province, Hangzhou Medical College, Hangzhou, China. FAU - Shi, Yuhua AU - Shi Y AD - Key Laboratory of Drug Safety Evaluation and Research of Zhejiang Province, Center of Safety Evaluation and Research, Hangzhou Medical College, Hangzhou, China. AD - Engineering Research Center of Novel Vaccine of Zhejiang Province, Hangzhou Medical College, Hangzhou, China. FAU - Zhang, Lili AU - Zhang L AD - Key Laboratory of Drug Safety Evaluation and Research of Zhejiang Province, Center of Safety Evaluation and Research, Hangzhou Medical College, Hangzhou, China. AD - Engineering Research Center of Novel Vaccine of Zhejiang Province, Hangzhou Medical College, Hangzhou, China. FAU - Shao, Jinjin AU - Shao J AD - Key Laboratory of Drug Safety Evaluation and Research of Zhejiang Province, Center of Safety Evaluation and Research, Hangzhou Medical College, Hangzhou, China. AD - Engineering Research Center of Novel Vaccine of Zhejiang Province, Hangzhou Medical College, Hangzhou, China. FAU - Chen, Yunxiang AU - Chen Y AD - Key Laboratory of Drug Safety Evaluation and Research of Zhejiang Province, Center of Safety Evaluation and Research, Hangzhou Medical College, Hangzhou, China. AD - Engineering Research Center of Novel Vaccine of Zhejiang Province, Hangzhou Medical College, Hangzhou, China. FAU - Pan, Xin AU - Pan X AD - Zhejiang Key Laboratory of Cell-Based Drug and Applied Technology Development, S-Evans Biosciences Co, Ltd., Hangzhou, China. FAU - Wu, Feifei AU - Wu F AD - Zhejiang Key Laboratory of Cell-Based Drug and Applied Technology Development, S-Evans Biosciences Co, Ltd., Hangzhou, China. FAU - Pan, Ruolang AU - Pan R AD - Zhejiang Key Laboratory of Cell-Based Drug and Applied Technology Development, S-Evans Biosciences Co, Ltd., Hangzhou, China. FAU - Liang, Jinfeng AU - Liang J AD - Zhejiang Center for Drugs and Cosmetics Evaluation, Zhejiang Province Food and Drug Administration, Hangzhou, China. FAU - Zhang, Lijiang AU - Zhang L AD - Key Laboratory of Drug Safety Evaluation and Research of Zhejiang Province, Center of Safety Evaluation and Research, Hangzhou Medical College, Hangzhou, China. AD - Engineering Research Center of Novel Vaccine of Zhejiang Province, Hangzhou Medical College, Hangzhou, China. LA - eng PT - Journal Article DEP - 20231025 PL - Switzerland TA - Front Cell Dev Biol JT - Frontiers in cell and developmental biology JID - 101630250 PMC - PMC10630163 OTO - NOTNLM OT - cynomolgus monkeys OT - immunosuppression OT - intravenous and subcutaneous injection OT - repeat-dose toxicity OT - umbilical cord mesenchymal stem cells COIS- Authors XP, FW, and RP were employed by S-Evans Biosciences Co, Ltd. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. EDAT- 2023/11/29 18:42 MHDA- 2023/11/29 18:43 PMCR- 2023/01/01 CRDT- 2023/11/29 14:54 PHST- 2023/08/07 00:00 [received] PHST- 2023/10/10 00:00 [accepted] PHST- 2023/11/29 18:43 [medline] PHST- 2023/11/29 18:42 [pubmed] PHST- 2023/11/29 14:54 [entrez] PHST- 2023/01/01 00:00 [pmc-release] AID - 1273723 [pii] AID - 10.3389/fcell.2023.1273723 [doi] PST - epublish SO - Front Cell Dev Biol. 2023 Oct 25;11:1273723. doi: 10.3389/fcell.2023.1273723. eCollection 2023.