The Abnormal Proliferation of Midbrain Dopamine Cells From Human Pluripotent Stem Cells Is Induced by Exposure to the Tumor Microenvironment
Jun Xue
Department of Neurosurgery, Huashan Hospital, MOE Frontiers Center for Brain Science, Fudan University, Shanghai, China
National Center for Neurological Disorders, Shanghai Key Laboratory of Brain Function and Restoration and Neural Regeneration, Huashan Hospital, Fudan University, Shanghai, China
Search for more papers by this authorDongyan Wu
Institute of Neurology, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, China
National Clinical Research Center for Aging and Medicine, Huashan Hospital, Fudan University, Shanghai, China
Search for more papers by this authorYuting Bao
Department of Neurosurgery, Huashan Hospital, MOE Frontiers Center for Brain Science, Fudan University, Shanghai, China
National Center for Neurological Disorders, Shanghai Key Laboratory of Brain Function and Restoration and Neural Regeneration, Huashan Hospital, Fudan University, Shanghai, China
Search for more papers by this authorYifan Wu
Department of Neurosurgery, Huashan Hospital, MOE Frontiers Center for Brain Science, Fudan University, Shanghai, China
National Center for Neurological Disorders, Shanghai Key Laboratory of Brain Function and Restoration and Neural Regeneration, Huashan Hospital, Fudan University, Shanghai, China
Search for more papers by this authorCorresponding Author
Xin Zhang
Department of Neurosurgery, Huashan Hospital, MOE Frontiers Center for Brain Science, Fudan University, Shanghai, China
National Center for Neurological Disorders, Shanghai Key Laboratory of Brain Function and Restoration and Neural Regeneration, Huashan Hospital, Fudan University, Shanghai, China
Correspondence:
Xin Zhang ([email protected])
Liang Chen ([email protected])
Search for more papers by this authorCorresponding Author
Liang Chen
Department of Neurosurgery, Huashan Hospital, MOE Frontiers Center for Brain Science, Fudan University, Shanghai, China
National Center for Neurological Disorders, Shanghai Key Laboratory of Brain Function and Restoration and Neural Regeneration, Huashan Hospital, Fudan University, Shanghai, China
Correspondence:
Xin Zhang ([email protected])
Liang Chen ([email protected])
Search for more papers by this authorJun Xue
Department of Neurosurgery, Huashan Hospital, MOE Frontiers Center for Brain Science, Fudan University, Shanghai, China
National Center for Neurological Disorders, Shanghai Key Laboratory of Brain Function and Restoration and Neural Regeneration, Huashan Hospital, Fudan University, Shanghai, China
Search for more papers by this authorDongyan Wu
Institute of Neurology, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, China
National Clinical Research Center for Aging and Medicine, Huashan Hospital, Fudan University, Shanghai, China
Search for more papers by this authorYuting Bao
Department of Neurosurgery, Huashan Hospital, MOE Frontiers Center for Brain Science, Fudan University, Shanghai, China
National Center for Neurological Disorders, Shanghai Key Laboratory of Brain Function and Restoration and Neural Regeneration, Huashan Hospital, Fudan University, Shanghai, China
Search for more papers by this authorYifan Wu
Department of Neurosurgery, Huashan Hospital, MOE Frontiers Center for Brain Science, Fudan University, Shanghai, China
National Center for Neurological Disorders, Shanghai Key Laboratory of Brain Function and Restoration and Neural Regeneration, Huashan Hospital, Fudan University, Shanghai, China
Search for more papers by this authorCorresponding Author
Xin Zhang
Department of Neurosurgery, Huashan Hospital, MOE Frontiers Center for Brain Science, Fudan University, Shanghai, China
National Center for Neurological Disorders, Shanghai Key Laboratory of Brain Function and Restoration and Neural Regeneration, Huashan Hospital, Fudan University, Shanghai, China
Correspondence:
Xin Zhang ([email protected])
Liang Chen ([email protected])
Search for more papers by this authorCorresponding Author
Liang Chen
Department of Neurosurgery, Huashan Hospital, MOE Frontiers Center for Brain Science, Fudan University, Shanghai, China
National Center for Neurological Disorders, Shanghai Key Laboratory of Brain Function and Restoration and Neural Regeneration, Huashan Hospital, Fudan University, Shanghai, China
Correspondence:
Xin Zhang ([email protected])
Liang Chen ([email protected])
Search for more papers by this authorFunding: This work was supported by National Natural Science Foundation of China (82272116) and China Postdoctoral Science Foundation (2024M750539).
Jun Xue and Dongyan Wu contributed equally to this work.
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.
Conflicts of Interest
The authors declare no conflicts of interest.
Open Research
Data Availability Statement
The data that support the findings of this study are available from the corresponding author upon reasonable request. The raw data of RNA-sequencing is available on the database of Sequence Read Archive (PRJNA1066752).
Supporting Information
| Filename | Description |
|---|---|
| cns70117-sup-0001-Supinfo.docxWord 2007 document , 2.9 MB |
Data S1. |
Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
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