A tumorigenicity evaluation platform for cell therapies based on brain organoids.

Autor: Xue J; Department of Neurosurgery, Huashan Hospital, MOE Frontiers Center for Brain Science, Fudan University, Shanghai, 200040, China.; National Center for Neurological Disorders, Shanghai Key Laboratory of Brain Function and Restoration and Neural Regeneration, Huashan Hospital, Fudan University, Shanghai, 200040, China., Chu Y; Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, Shanghai, 201210, China., Huang Y; Department of Neurosurgery, Huashan Hospital, MOE Frontiers Center for Brain Science, Fudan University, Shanghai, 200040, China.; National Center for Neurological Disorders, Shanghai Key Laboratory of Brain Function and Restoration and Neural Regeneration, Huashan Hospital, Fudan University, Shanghai, 200040, China., Chen M; Department of Neurosurgery, Huashan Hospital, MOE Frontiers Center for Brain Science, Fudan University, Shanghai, 200040, China.; National Center for Neurological Disorders, Shanghai Key Laboratory of Brain Function and Restoration and Neural Regeneration, Huashan Hospital, Fudan University, Shanghai, 200040, China., Sun M; Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, Shanghai, 201210, China., Fan Z; Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, Shanghai, 201210, China., Wu Y; Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, Shanghai, 201210, China. wuyh2@shanghaitech.edu.cn.; Shanghai Clinical Research and Trial Center, Shanghai, 201210, China. wuyh2@shanghaitech.edu.cn., Chen L; Department of Neurosurgery, Huashan Hospital, MOE Frontiers Center for Brain Science, Fudan University, Shanghai, 200040, China. chenlianghs@126.com.; National Center for Neurological Disorders, Shanghai Key Laboratory of Brain Function and Restoration and Neural Regeneration, Huashan Hospital, Fudan University, Shanghai, 200040, China. chenlianghs@126.com.
Jazyk: angličtina
Zdroj: Translational neurodegeneration [Transl Neurodegener] 2024 Oct 29; Vol. 13 (1), pp. 53. Date of Electronic Publication: 2024 Oct 29.
DOI: 10.1186/s40035-024-00446-5
Abstrakt: Background: Tumorigenicity represents a critical challenge in stem cell-based therapies requiring rigorous monitoring. Conventional approaches for tumorigenicity evaluation are based on animal models and have numerous limitations. Brain organoids, which recapitulate the structural and functional complexity of the human brain, have been widely used in neuroscience research. However, the capacity of brain organoids for tumorigenicity evaluation needs to be further elucidated.
Methods: A cerebral organoid model produced from human pluripotent stem cells (hPSCs) was employed. Meanwhile, to enhance the detection sensitivity for potential tumorigenic cells, we created a glioblastoma-like organoid (GBM organoid) model from TP53 -/- /PTEN -/- hPSCs to provide a tumor microenvironment for injected cells. Midbrain dopamine (mDA) cells from human embryonic stem cells were utilized as a cell therapy product. mDA cells, hPSCs, mDA cells spiked with hPSCs, and immature mDA cells were then injected into the brain organoids and NOD SCID mice. The injected cells within the brain organoids were characterized, and compared with those injected in vivo to evaluate the capability of the brain organoids for tumorigenicity evaluation. Single-cell RNA sequencing was performed to identify the differential gene expression between the cerebral organoids and the GBM organoids.
Results: Both cerebral organoids and GBM organoids supported maturation of the injected mDA cells. The hPSCs and immature mDA cells injected in the GBM organoids showed a significantly higher proliferative capacity than those injected in the cerebral organoids and in NOD SCID mice. Furthermore, the spiked hPSCs were detectable in both the cerebral organoids and the GBM organoids. Notably, the GBM organoids demonstrated a superior capacity to enhance proliferation and pluripotency of spiked hPSCs compared to the cerebral organoids and the mouse model. Kyoto Encyclopedia of Genes and Genomes analysis revealed upregulation of tumor-related metabolic pathways and cytokines in the GBM organoids, suggesting that these factors underlie the high detection sensitivity for tumorigenicity evaluation.
Conclusions: Our findings suggest that brain organoids could represent a novel and effective platform for evaluating the tumorigenic risk in stem cell-based therapies. Notably, the GBM organoids offer a superior platform that could complement or potentially replace traditional animal-based models for tumorigenicity evaluation.
(© 2024. The Author(s).)
Databáze: MEDLINE
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