The Abnormal Proliferation of Midbrain Dopamine Cells From Human Pluripotent Stem Cells Is Induced by Exposure to the Tumor Microenvironment

IF 4.8 1区医学 Q1 NEUROSCIENCES

CNS Neuroscience & Therapeutics Pub Date : 2024-11-19 DOI:10.1111/cns.70117

Jun Xue, Dongyan Wu, Yuting Bao, Yifan Wu, Xin Zhang, Liang Chen

{"title":"The Abnormal Proliferation of Midbrain Dopamine Cells From Human Pluripotent Stem Cells Is Induced by Exposure to the Tumor Microenvironment","authors":"Jun Xue, Dongyan Wu, Yuting Bao, Yifan Wu, Xin Zhang, Liang Chen","doi":"10.1111/cns.70117","DOIUrl":null,"url":null,"abstract":"<div>\n \n \n <section>\n \n <h3> Aims</h3>\n \n <p>Tumorigenicity is a significant concern in stem cell-based therapies. However, traditional tumorigenicity tests using animal models often produce inaccurate results. Consequently, a more sensitive method for assessing tumorigenicity is required. This study aimed to enhance sensitivity by exposing functional progenitors derived from human pluripotent stem cells (hPSCs) to the tumor microenvironment (TME) in vitro before transplantation, potentially making them more prone to abnormal proliferation or tumorigenicity.</p>\n </section>\n \n <section>\n \n <h3> Methods</h3>\n \n <p>Midbrain dopamine (mDA) cells derived from hPSCs were exposed to the TME by coculturing with medulloblastoma. The cellular characteristics of these cocultured mDA cells were evaluated both in vitro and in vivo, and the mechanisms underlying the observed alterations were investigated.</p>\n </section>\n \n <section>\n \n <h3> Results</h3>\n \n <p>Our findings demonstrated increased proliferation of cocultured mDA cells both in vitro and in vivo. Moreover, these proliferating cells showed a higher expression of Ki67 and SOX1, suggesting abnormal proliferation. The observed abnormal proliferation in cocultured mDA cells was attributed to the hyperactivation of proliferation-related genes, the JAK/STAT3 pathway, and cytokine stimulation.</p>\n </section>\n \n <section>\n \n <h3> Conclusion</h3>\n \n <p>This study indicates that exposing functional progenitors to the TME in vitro before transplantation can induce abnormal proliferation, thereby increasing the sensitivity of tumorigenicity tests.</p>\n </section>\n </div>","PeriodicalId":154,"journal":{"name":"CNS Neuroscience & Therapeutics","volume":"30 11","pages":""},"PeriodicalIF":4.8000,"publicationDate":"2024-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cns.70117","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"CNS Neuroscience & Therapeutics","FirstCategoryId":"3","ListUrlMain":"https://onlinelibrary.wiley.com/doi/10.1111/cns.70117","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"NEUROSCIENCES","Score":null,"Total":0}

引用次数: 0

Abstract

Aims

Tumorigenicity is a significant concern in stem cell-based therapies. However, traditional tumorigenicity tests using animal models often produce inaccurate results. Consequently, a more sensitive method for assessing tumorigenicity is required. This study aimed to enhance sensitivity by exposing functional progenitors derived from human pluripotent stem cells (hPSCs) to the tumor microenvironment (TME) in vitro before transplantation, potentially making them more prone to abnormal proliferation or tumorigenicity.

Methods

Midbrain dopamine (mDA) cells derived from hPSCs were exposed to the TME by coculturing with medulloblastoma. The cellular characteristics of these cocultured mDA cells were evaluated both in vitro and in vivo, and the mechanisms underlying the observed alterations were investigated.

Results

Our findings demonstrated increased proliferation of cocultured mDA cells both in vitro and in vivo. Moreover, these proliferating cells showed a higher expression of Ki67 and SOX1, suggesting abnormal proliferation. The observed abnormal proliferation in cocultured mDA cells was attributed to the hyperactivation of proliferation-related genes, the JAK/STAT3 pathway, and cytokine stimulation.

Conclusion

This study indicates that exposing functional progenitors to the TME in vitro before transplantation can induce abnormal proliferation, thereby increasing the sensitivity of tumorigenicity tests.

查看原文本刊更多论文

肿瘤微环境诱导人多能干细胞中脑多巴胺细胞异常增殖

目的致癌性是干细胞疗法的一个重要问题。然而，使用动物模型进行的传统致瘤性测试往往产生不准确的结果。因此，需要一种更灵敏的方法来评估致瘤性。本研究旨在通过在移植前将源自人类多能干细胞（hPSCs）的功能性祖细胞暴露于体外肿瘤微环境（TME），使其更容易异常增殖或致瘤，从而提高灵敏度。方法通过与髓母细胞瘤共培养，将源自 hPSCs 的中脑多巴胺（mDA）细胞暴露于肿瘤微环境。在体外和体内评估了这些共培养的 mDA 细胞的细胞特性，并研究了观察到的变化的机制。结果我们的研究结果表明，体外和体内共同培养的 mDA 细胞的增殖均有所增加。此外，这些增殖细胞的 Ki67 和 SOX1 表达量较高，表明增殖异常。在共培养的 mDA 细胞中观察到的异常增殖可归因于增殖相关基因、JAK/STAT3 通路和细胞因子刺激的过度激活。结论本研究表明，在移植前将功能性祖细胞暴露于体外 TME 可诱导异常增殖，从而提高致瘤性检测的敏感性。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文求助全文

来源期刊

CNS Neuroscience & Therapeutics 医学-神经科学

CiteScore

7.30

自引率

12.70%

发文量

240

审稿时长

2 months

期刊介绍： CNS Neuroscience & Therapeutics provides a medium for rapid publication of original clinical, experimental, and translational research papers, timely reviews and reports of novel findings of therapeutic relevance to the central nervous system, as well as papers related to clinical pharmacology, drug development and novel methodologies for drug evaluation. The journal focuses on neurological and psychiatric diseases such as stroke, Parkinson’s disease, Alzheimer’s disease, depression, schizophrenia, epilepsy, and drug abuse.