Developing a human iPSC-derived three-dimensional myelin spheroid platform for modeling myelin diseases
Lizhao Feng,
Jianfei Chao,
Mingzi Zhang,
Elizabeth Pacquing,
Weidong Hu,
Yanhong Shi
Affiliations
Lizhao Feng
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
Jianfei Chao
Department of Neurodegenerative Diseases, Beckman Research Institute of City of Hope, 1500 E. Duarte Road, Duarte, CA 91010, USA
Mingzi Zhang
Department of Neurodegenerative Diseases, Beckman Research Institute of City of Hope, 1500 E. Duarte Road, Duarte, CA 91010, USA
Elizabeth Pacquing
Department of Neurodegenerative Diseases, Beckman Research Institute of City of Hope, 1500 E. Duarte Road, Duarte, CA 91010, USA
Weidong Hu
Department of Molecular Imaging and Therapy, Beckman Research Institute of City of Hope, 1500 E. Duarte Road, Duarte, CA 91010, USA
Yanhong Shi
Department of Neurodegenerative Diseases, Beckman Research Institute of City of Hope, 1500 E. Duarte Road, Duarte, CA 91010, USA; Corresponding author
Summary: 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.
