Wang Xin, Pei Zifei, Hossain Aasma, Bai Yuting, Chen Gong
Department of Biology, Huck Institutes of Life Sciences, Pennsylvania State University, University Park, PA 16802, USA.
GHM Institute of CNS Regeneration, Jinan University, Guangzhou 510632, China.
Cancer Biol Med. 2021 Mar 23;18(3):860-74. doi: 10.20892/j.issn.2095-3941.2020.0499.
Glioblastoma (GBM) is the most prevalent and aggressive adult primary cancer in the central nervous system. Therapeutic approaches for GBM treatment are under intense investigation, including the use of emerging immunotherapies. Here, we propose an alternative approach to treat GBM through reprogramming proliferative GBM cells into non-proliferative neurons.
Retroviruses were used to target highly proliferative human GBM cells through overexpression of neural transcription factors. Immunostaining, electrophysiological recording, and bulk RNA-seq were performed to investigate the mechanisms underlying the neuronal conversion of human GBM cells. An intracranial xenograft mouse model was used to examine the neuronal conversion of human GBM cells.
We report efficient neuronal conversion from human GBM cells by overexpressing single neural transcription factor Neurogenic differentiation 1 (NeuroD1), Neurogenin-2 (Neurog2), or Achaete-scute homolog 1 (Ascl1). Subtype characterization showed that the majority of Neurog2- and NeuroD1-converted neurons were glutamatergic, while Ascl1 favored GABAergic neuron generation. The GBM cell-converted neurons not only showed pan-neuronal markers but also exhibited neuron-specific electrophysiological activities. Transcriptome analyses revealed that neuronal genes were activated in glioma cells after overexpression of neural transcription factors, and different signaling pathways were activated by different neural transcription factors. Importantly, the neuronal conversion of GBM cells was accompanied by significant inhibition of GBM cell proliferation in both and models.
These results suggest that GBM cells can be reprogrammed into different subtypes of neurons, leading to a potential alternative approach to treat brain tumors using cell conversion technology.
胶质母细胞瘤（GBM）是中枢神经系统中最常见且侵袭性最强的成人原发性癌症。针对GBM治疗的方法正在深入研究中，包括使用新兴的免疫疗法。在此，我们提出一种通过将增殖性GBM细胞重编程为非增殖性神经元来治疗GBM的替代方法。
利用逆转录病毒通过过表达神经转录因子来靶向高度增殖的人GBM细胞。进行免疫染色、电生理记录和大量RNA测序以研究人GBM细胞神经元转化的潜在机制。使用颅内异种移植小鼠模型来检测人GBM细胞的神经元转化。
我们报告称，通过过表达单一神经转录因子神经源性分化1（NeuroD1）、神经生成素-2（Neurog2）或achaete-scute同源物1（Ascl1），可使人GBM细胞高效地发生神经元转化。亚型特征分析表明，大多数由Neurog2和NeuroD1转化而来的神经元是谷氨酸能的，而Ascl1则有利于生成γ-氨基丁酸能神经元。GBM细胞转化而来的神经元不仅显示出泛神经元标志物，还表现出神经元特异性电生理活动。转录组分析显示，在神经转录因子过表达后，神经基因在胶质瘤细胞中被激活，并且不同的神经转录因子激活不同的信号通路。重要的是，在体外和体内模型中，GBM细胞的神经元转化都伴随着GBM细胞增殖的显著抑制。
这些结果表明，GBM细胞可被重编程为不同亚型的神经元，这为利用细胞转化技术治疗脑肿瘤提供了一种潜在的替代方法。
