Large-scale differentiation of iPSC-derived motor neurons from ALS and control subjects

Michael J Workman; Ryan G Lim; Jie Wu; Aaron Frank; Loren Ornelas; Lindsay Panther; Erick Galvez; Daniel Perez; Imara Meepe; Susan Lei; Viviana Valencia; Emilda Gomez; Chunyan Liu; Ruby Moran; Louis Pinedo; Stanislav Tsitkov; Ritchie Ho; Julia A Kaye; Answer ALS Consortium; Terri Thompson; Jeffrey D Rothstein; Steven Finkbeiner; Ernest Fraenkel; Dhruv Sareen; Leslie M Thompson; Clive N Svendsen

doi:10.1016/j.neuron.2023.01.010

Large-scale differentiation of iPSC-derived motor neurons from ALS and control subjects

Neuron. 2023 Apr 19;111(8):1191-1204.e5. doi: 10.1016/j.neuron.2023.01.010. Epub 2023 Feb 9.

Authors

Michael J Workman¹, Ryan G Lim², Jie Wu³, Aaron Frank⁴, Loren Ornelas⁴, Lindsay Panther⁴, Erick Galvez⁴, Daniel Perez⁴, Imara Meepe⁴, Susan Lei⁴, Viviana Valencia⁴, Emilda Gomez⁴, Chunyan Liu⁴, Ruby Moran⁴, Louis Pinedo⁴, Stanislav Tsitkov⁵, Ritchie Ho⁶, Julia A Kaye⁷; Answer ALS Consortium; Terri Thompson⁸, Jeffrey D Rothstein⁹, Steven Finkbeiner⁷, Ernest Fraenkel⁵, Dhruv Sareen¹⁰, Leslie M Thompson¹¹, Clive N Svendsen¹²

Affiliations

¹ The Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
² Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, CA, USA.
³ Department of Biological Chemistry, University of California, Irvine, CA, USA.
⁴ Cedars-Sinai Biomanufacturing Center, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
⁵ Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA.
⁶ The Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA; Center for Neural Science and Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA; Department of Neurology, Cedars-Sinai Medical Center, Los Angeles, CA, USA; Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
⁷ Center for Systems and Therapeutics, Gladstone Institutes, University of California, San Francisco, San Francisco, CA, USA; Taube/Koret Center for Neurodegenerative Disease, Gladstone Institutes, University of California, San Francisco, San Francisco, CA, USA; Departments of Neurology and Physiology, University of California, San Francisco, San Francisco, CA, USA.
⁸ On Point Scientific Inc., San Diego, CA, USA.
⁹ Brain Science Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
¹⁰ The Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA; Cedars-Sinai Biomanufacturing Center, Cedars-Sinai Medical Center, Los Angeles, CA, USA. Electronic address: dhruv.sareen@cshs.org.
¹¹ Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, CA, USA; Department of Biological Chemistry, University of California, Irvine, CA, USA; Department of Neurobiology and Behavior, University of California, Irvine, CA, USA; Department of Psychiatry and Human Behavior and Sue and Bill Gross Stem Cell Center, University of California, Irvine, CA, USA. Electronic address: lmthomps@uci.edu.
¹² The Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA; Cedars-Sinai Biomanufacturing Center, Cedars-Sinai Medical Center, Los Angeles, CA, USA. Electronic address: clive.svendsen@cshs.org.

Abstract

Using induced pluripotent stem cells (iPSCs) to understand the mechanisms of neurological disease holds great promise; however, there is a lack of well-curated lines from a large array of participants. Answer ALS has generated over 1,000 iPSC lines from control and amyotrophic lateral sclerosis (ALS) patients along with clinical and whole-genome sequencing data. The current report summarizes cell marker and gene expression in motor neuron cultures derived from 92 healthy control and 341 ALS participants using a 32-day differentiation protocol. This is the largest set of iPSCs to be differentiated into motor neurons, and characterization suggests that cell composition and sex are significant sources of variability that need to be carefully controlled for in future studies. These data are reported as a resource for the scientific community that will utilize Answer ALS data for disease modeling using a wider array of omics being made available for these samples.

Keywords: ALS; iPSC; motor neurons; sex differences.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

MeSH terms

Amyotrophic Lateral Sclerosis* / genetics
Amyotrophic Lateral Sclerosis* / metabolism
Cell Differentiation
Humans
Induced Pluripotent Stem Cells* / metabolism
Motor Neurons / metabolism

Abstract

Publication types

MeSH terms

Grants and funding