Large-Scale Generation and Characterization of Homogeneous Populations of Migratory Cortical Interneurons from Human Pluripotent Stem Cells

Authors

Peiyan Ni
Haneul Noh
Zhicheng Shao
Qian Zhu, New York Medical CollegeFollow
Youxin Guan, New York Medical College
Joshua J. Park, New York Medical CollegeFollow
Fatima Arif, New York Medical College
James M. Park, New York Medical CollegeFollow
Chiderah Abani, New York Medical CollegeFollow
Cameron Beaudreault, New York Medical College
Joy S. Park, New York Medical CollegeFollow
Elizabeth Berry, New York Medical College
Alexander Moghadam, New York Medical College
Patric Stanton, New York Medical CollegeFollow
Leonard Eisenberg, New York Medical CollegeFollow
Sangmi Chung, New York Medical CollegeFollow
Clare Faux
John Parnevelas
Leonard M. Eisenberg, New York Medical CollegeFollow
Kyungjoon Park
Vadim Y. Bolshakov
Sangmi Chung, New York Medical CollegeFollow

DOI

10.1016/j.omtm.2019.04.002

Journal Title

Molecular Therapy. Methods & Clinical Development

First Page

414

Last Page

430

Document Type

Article

Publication Date

April 2019

Department

Cell Biology and Anatomy

Abstract

During development, cortical interneurons (cINs) are generated from the ventral telencephalon, robustly migrate to the dorsal telencephalon, make local synaptic connections, and critically regulate brain circuitry by inhibiting other neurons. Thus, their abnormality is associated with various brain disorders. Human pluripotent stem cell (hPSC)-derived cINs can provide unlimited sources with which to study the pathogenesis mechanism of these disorders as well as provide a platform to develop novel therapeutics. By employing spinner culture, we could obtain a >10-fold higher yield of cIN progenitors compared to conventional culture without affecting their phenotype. Generated cIN spheres can be maintained feeder-free up to 10 months and are optimized for passaging and cryopreservation. In addition, we identified a combination of chemicals that synchronously matures generated progenitors into SOX6(+)KI67(-) migratory cINs and extensively characterized their maturation in terms of metabolism, migration, arborization, and electrophysiology. When transplanted into mouse brains, chemically matured migratory cINs generated grafts that efficiently disperse and integrate into the host circuitry without uncontrolled growth, making them an optimal cell population for cell therapy. Efficient large-scale generation of homogeneous migratory cINs without the need of feeder cells will play a critical role in the full realization of hPSC-derived cINs for development of novel therapeutics.

Comments

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Recommended Citation

Ni, P., Noh, H., Shao, Z., Zhu, Q., Guan, Y., Park, J. J., Arif, F., Park, J., Abani, C., Beaudreault, C., Park, J. S., Berry, E., Moghadam, A., Stanton, P., Eisenberg, L., Chung, S., Faux, C., Parnevelas, J., Eisenberg, L., Park, K., Bolshakov, V., & Chung, S. (2019). Large-Scale Generation and Characterization of Homogeneous Populations of Migratory Cortical Interneurons from Human Pluripotent Stem Cells. Molecular Therapy. Methods & Clinical Development, 13, 414-430. https://doi.org/10.1016/j.omtm.2019.04.002