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

Publisher: Wiley-Blackwell Country of Publication: England NLM ID: 101473265 Publication Model: Print Cited Medium: Internet ISSN: 1755-5949 (Electronic) Linking ISSN: 17555930 NLM ISO Abbreviation: CNS Neurosci Ther Subsets: MEDLINE

Original Publication: Oxford, UK : Wiley-Blackwell, c2008-

Tumor Microenvironment*/physiology ; Cell Proliferation*/physiology ; Mesencephalon*/cytology ; Mesencephalon*/metabolism ; Pluripotent Stem Cells* ; Dopaminergic Neurons*/metabolism ; Dopaminergic Neurons*/pathology ; Coculture Techniques* ; Medulloblastoma*/pathology ; Medulloblastoma*/metabolism; Humans ; Animals ; Mice ; Cerebellar Neoplasms/pathology ; Cerebellar Neoplasms/metabolism

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.
(© 2024 The Author(s). CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd.)

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82272116 National Natural Science Foundation of China; 2024M750539 China Postdoctoral Science Foundation

Keywords: cell therapies; coculture; midbrain dopamine cells; tumor microenvironment; tumorigenicity tests

Date Created: 20241120 Date Completed: 20241120 Latest Revision: 20241123

20241123

PMC11576488

10.1111/cns.70117

39563017