Study on Preclinical Safety and Toxic Mechanism of Human Umbilical Cord Mesenchymal Stem Cells in F344RG Rats.

IF 4.5 3区 医学 Q2 CELL & TISSUE ENGINEERING
Stem Cell Reviews and Reports Pub Date : 2024-11-01 Epub Date: 2024-09-07 DOI:10.1007/s12015-024-10780-w
Xiaofang Hao, Hao Zhu, Chao Qin, Lulu Li, Zhi Lin, Hua Jiang, Qianqian Li, Yan Huo, Hezhan Zhang, Xingchao Geng, Ying Huang, Bo Li
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引用次数: 0

Abstract

Mesenchymal stem cells have made remarkable progress in recent years. Many studies have reported that human umbilical cord mesenchymal stem cells (hUC-MSCs) have no toxicity, but thromboembolism appeared in patients treated with hUC-MSCs. Therefore, people are still worried about the safety of clinical application. The study aims to determine the safety, potential toxic mechanism and biodistribution of hUC-MSCs. F344RG rats were given 5 or 50 million cells/kg of hUC-MSCs by single administration in compliance with Good Laboratory Practice standards. Standard toxicity was performed. RNA sequencing was then performed to explore the potential toxic mechanisms. In parallel, the biodistribution of hUC-MSCs was examined. The dose of 5 million cells/kg hUC-MSCs had no obvious toxicity on symptom, weight, food intake, hematology, serum biochemistry, urine biochemistry, cytokines, and histopathology. However, blood-tinged secretions in the urethral orifice and 20% mortality occurred at 50 million cells/kg. Disseminated intravascular coagulopathy (DIC) is the leading cause of death. hUC-MSCs significantly upregulated complement and coagulation cascade pathways gene expression, resulting in DIC. Besides, hUC-MSCs upregulated fibrinolytic system suppressor genes A2m, Serping1 and Serpinf2. hUC-MSCs survived in rats for less than 28 days, no hUC-MSC was detected in tissues outside the lungs. There was no toxicity in F344RG rats at 5 million cells/kg, but some toxicities were detected at 50 million cells/kg. hUC-MSCs significantly upregulated complement and coagulation cascade pathways, upregulated the expression of fibrinolytic system suppressor genes A2m, Serping1 and Serpinf2, to inhibit fibrinolytic system, caused DIC, which provided a new insight into the toxic mechanism of hUC-MSCs.

Abstract Image

人脐间质干细胞在 F344RG 大鼠中的临床前安全性和毒性机制研究
间充质干细胞近年来取得了显著进展。许多研究报道,人脐带间充质干细胞(hUC-MSCs)无毒性,但使用hUC-MSCs治疗的患者出现血栓栓塞。因此,人们仍然担心临床应用的安全性。本研究旨在确定 hUC-MSCs 的安全性、潜在毒性机制和生物分布。按照 "良好实验室规范 "标准,给 F344RG 大鼠单次注射 500 万或 5000 万个细胞/千克的 hUC-间充质干细胞。进行了标准毒性测试。然后进行 RNA 测序,以探索潜在的毒性机制。与此同时,还对 hUC-MSCs 的生物分布进行了检测。剂量为500万个细胞/千克的hUC-间充质干细胞对症状、体重、进食量、血液学、血清生化学、尿液生化学、细胞因子和组织病理学均无明显毒性。然而,在 5000 万个细胞/千克时,尿道口会出现带血的分泌物,死亡率为 20%。播散性血管内凝血病(DIC)是导致死亡的主要原因。hUC-间充质干细胞能显著上调补体和凝血级联途径基因的表达,从而导致DIC。此外,hUC-间充质干细胞还能上调纤溶系统抑制基因 A2m、Serping1 和 Serpinf2。hUC-间充质干细胞显著上调补体和凝血级联通路,上调纤溶系统抑制基因A2m、Serping1和Serpinf2的表达,抑制纤溶系统,导致DIC,这为了解hUC-间充质干细胞的毒性机制提供了新的视角。
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来源期刊
Stem Cell Reviews and Reports
Stem Cell Reviews and Reports 医学-细胞生物学
CiteScore
9.30
自引率
4.20%
发文量
0
审稿时长
3 months
期刊介绍: The purpose of Stem Cell Reviews and Reports is to cover contemporary and emerging areas in stem cell research and regenerative medicine. The journal will consider for publication: i) solicited or unsolicited reviews of topical areas of stem cell biology that highlight, critique and synthesize recent important findings in the field. ii) full length and short reports presenting original experimental work. iii) translational stem cell studies describing results of clinical trials using stem cells as therapeutics. iv) papers focused on diseases of stem cells. v) hypothesis and commentary articles as opinion-based pieces in which authors can propose a new theory, interpretation of a controversial area in stem cell biology, or a stem cell biology question or paradigm. These articles contain more speculation than reviews, but they should be based on solid rationale. vi) protocols as peer-reviewed procedures that provide step-by-step descriptions, outlined in sufficient detail, so that both experts and novices can apply them to their own research. vii) letters to the editor and correspondence. In order to facilitate this exchange of scientific information and exciting novel ideas, the journal has created five thematic sections, focusing on: i) the role of adult stem cells in tissue regeneration; ii) progress in research on induced pluripotent stem cells, embryonic stem cells and mechanism governing embryogenesis and tissue development; iii) the role of microenvironment and extracellular microvesicles in directing the fate of stem cells; iv) mechanisms of stem cell trafficking, stem cell mobilization and homing with special emphasis on hematopoiesis; v) the role of stem cells in aging processes and cancerogenesis.
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