Feng Lizhao, Chao Jianfei, Zhang Mingzi, Pacquing Elizabeth, Hu Weidong, Shi Yanhong
Department of Neurodegenerative Diseases, Beckman Research Institute of City of Hope, 1500 E. Duarte Road, Duarte, CA 91010, USA.
Oujiang Laboratory, Zhejiang Lab for Regenerative Medicine, Vision and Brain Health, Wenzhou, Zhejiang 325000, China.
iScience. 2023 Sep 25;26(11):108037. doi: 10.1016/j.isci.2023.108037. eCollection 2023 Nov 17.
Myelin defects cause a collection of myelin disorders in the brain. The lack of human models has limited us from better understanding pathological mechanisms of myelin diseases. While human induced pluripotent stem cell (hiPSC)-derived spheroids or organoids have been used to study brain development and disorders, it has been difficult to recapitulate mature myelination in these structures. Here, we have developed a method to generate three-dimensional (3D) myelin spheroids from hiPSCs in a robust and reproducible manner. Using this method, we generated myelin spheroids from patient iPSCs to model Canavan disease (CD), a demyelinating disorder. By using CD patient iPSC-derived myelin spheroids treated with N-acetyl-aspartate (NAA), we were able to recapitulate key pathological features of the disease and show that high-level NAA is sufficient to induce toxicity on myelin sheaths. Our study has established a 3D human cellular platform to model human myelin diseases for mechanistic studies and drug discovery.
髓鞘缺陷会引发一系列脑部髓鞘疾病。缺乏人类模型限制了我们对髓鞘疾病病理机制的深入理解。虽然人类诱导多能干细胞（hiPSC）来源的球体或类器官已被用于研究大脑发育和疾病，但在这些结构中很难重现成熟的髓鞘形成过程。在此，我们开发了一种方法，能够以稳健且可重复的方式从hiPSC生成三维（3D）髓鞘球体。利用该方法，我们从患者诱导多能干细胞中生成了髓鞘球体，用于模拟一种脱髓鞘疾病——卡纳万病（CD）。通过使用经N - 乙酰天门冬氨酸（NAA）处理的CD患者诱导多能干细胞来源的髓鞘球体，我们能够重现该疾病的关键病理特征，并表明高水平的NAA足以对髓鞘鞘膜产生毒性。我们的研究建立了一个3D人类细胞平台，用于模拟人类髓鞘疾病，以进行机制研究和药物发现。
