PMID- 37921457 OWN - NLM STAT- MEDLINE DCOM- 20231120 LR - 20231120 IS - 1744-7607 (Electronic) IS - 1742-5255 (Linking) VI - 19 IP - 11 DP - 2023 Jul-Dec TI - A repeat-dose toxicity study of human umbilical cord mesenchymal stem cells in NOG mice by intravenous injection. PG - 857-866 LID - 10.1080/17425255.2023.2279243 [doi] AB - BACKGROUND: Stem cell-based therapies have demonstrated great potential in several clinical trials. However, safety data on stem cell application remain inadequate. This study evaluated the toxicity of human umbilical cord mesenchymal stem cells (hUC-MSCs) in NOD/Shi-scid/IL-2 Rgamma(null) (NOG) mice. RESEARCH DESIGN AND METHODS: Mice were administered hUC-MSCs intravenously at doses of 3.5 x 10(6) cells/kg and 3.5 x 10(7) cells/kg. Toxicity was assessed by clinical observation, behavioral evaluation, pathology, organ weight, and histopathology. We determined the distribution of hUC-MSCs using a validated qPCR method and colonization using immunohistochemistry. RESULTS: No significant abnormal effects on clinical responses, body weight, or food intake were observed in the mice, except for two in the high-dose group that died during the last administration. Mouse activity in the high-dose group decreased 6 h after the first administration. Terminal examination revealed dose-dependent changes in hematology. The mice in the high-dose group displayed pulmonary artery wall plaques and mild alveolar wall microthrombi. hUC-MSCs colonized primarily the lung tissues and were largely distributed there 24 h after the final administration. CONCLUSIONS: The no observed adverse effect level for intravenous administration of hUC-MSCs in NOG mice over a period of 3 w was 3.5 x 10(6) cells/kg. FAU - Shao, Jinjin AU - Shao J AD - Center of Safety Evaluation and Research, Hangzhou Medical College, Hangzhou, China. AD - Key Laboratory of Drug Safety Evaluation and Research of Zhejiang Province, Hangzhou Medical College (Zhejiang Academy of Medical Sciences), Hangzhou, China. FAU - Xia, Lijuan AU - Xia L AD - Center of Safety Evaluation and Research, Hangzhou Medical College, Hangzhou, China. AD - Key Laboratory of Drug Safety Evaluation and Research of Zhejiang Province, Hangzhou Medical College (Zhejiang Academy of Medical Sciences), Hangzhou, China. FAU - Ye, Zhichao AU - Ye Z AD - Center of Safety Evaluation and Research, Hangzhou Medical College, Hangzhou, China. AD - Key Laboratory of Drug Safety Evaluation and Research of Zhejiang Province, Hangzhou Medical College (Zhejiang Academy of Medical Sciences), Hangzhou, China. FAU - Yang, Qian AU - Yang Q AD - Center of Safety Evaluation and Research, Hangzhou Medical College, Hangzhou, China. AD - Key Laboratory of Drug Safety Evaluation and Research of Zhejiang Province, Hangzhou Medical College (Zhejiang Academy of Medical Sciences), Hangzhou, China. FAU - Zhang, Chengda AU - Zhang C AD - Center of Safety Evaluation and Research, Hangzhou Medical College, Hangzhou, China. AD - Key Laboratory of Drug Safety Evaluation and Research of Zhejiang Province, Hangzhou Medical College (Zhejiang Academy of Medical Sciences), Hangzhou, China. FAU - Shi, Yuhua AU - Shi Y AD - Center of Safety Evaluation and Research, Hangzhou Medical College, Hangzhou, China. AD - Key Laboratory of Drug Safety Evaluation and Research of Zhejiang Province, Hangzhou Medical College (Zhejiang Academy of Medical Sciences), Hangzhou, China. FAU - Zhang, Lili AU - Zhang L AD - Center of Safety Evaluation and Research, Hangzhou Medical College, Hangzhou, China. AD - Key Laboratory of Drug Safety Evaluation and Research of Zhejiang Province, Hangzhou Medical College (Zhejiang Academy of Medical Sciences), Hangzhou, China. FAU - Gu, Liqiang AU - Gu L AD - Center of Safety Evaluation and Research, Hangzhou Medical College, Hangzhou, China. AD - Key Laboratory of Drug Safety Evaluation and Research of Zhejiang Province, Hangzhou Medical College (Zhejiang Academy of Medical Sciences), Hangzhou, China. FAU - Xu, Cong AU - Xu C AD - Center of Safety Evaluation and Research, Hangzhou Medical College, Hangzhou, China. AD - Key Laboratory of Drug Safety Evaluation and Research of Zhejiang Province, Hangzhou Medical College (Zhejiang Academy of Medical Sciences), Hangzhou, China. FAU - Chen, Ying AU - Chen Y AD - Center of Safety Evaluation and Research, Hangzhou Medical College, Hangzhou, China. AD - Key Laboratory of Drug Safety Evaluation and Research of Zhejiang Province, Hangzhou Medical College (Zhejiang Academy of Medical Sciences), Hangzhou, China. FAU - Chen, Yunxiang AU - Chen Y AD - Center of Safety Evaluation and Research, Hangzhou Medical College, Hangzhou, China. AD - Key Laboratory of Drug Safety Evaluation and Research of Zhejiang Province, Hangzhou Medical College (Zhejiang Academy of Medical Sciences), 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 - Center of Safety Evaluation and Research, Hangzhou Medical College, Hangzhou, China. AD - Key Laboratory of Drug Safety Evaluation and Research of Zhejiang Province, Hangzhou Medical College (Zhejiang Academy of Medical Sciences), Hangzhou, China. LA - eng PT - Journal Article DEP - 20231117 PL - England TA - Expert Opin Drug Metab Toxicol JT - Expert opinion on drug metabolism & toxicology JID - 101228422 SB - IM MH - Humans MH - Mice MH - Animals MH - Injections, Intravenous MH - *Umbilical Cord MH - Mice, Inbred NOD MH - Lung MH - *Mesenchymal Stem Cells/physiology OTO - NOTNLM OT - Human umbilical cord mesenchymal stem cells OT - NOG mice OT - colonization OT - distribution OT - repeat-dose toxicity EDAT- 2023/11/03 12:46 MHDA- 2023/11/20 06:55 CRDT- 2023/11/03 08:54 PHST- 2023/11/20 06:55 [medline] PHST- 2023/11/03 12:46 [pubmed] PHST- 2023/11/03 08:54 [entrez] AID - 10.1080/17425255.2023.2279243 [doi] PST - ppublish SO - Expert Opin Drug Metab Toxicol. 2023 Jul-Dec;19(11):857-866. doi: 10.1080/17425255.2023.2279243. Epub 2023 Nov 17.