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. 2015 Oct;82:269-280.
doi: 10.1016/j.nbd.2015.06.011. Epub 2015 Jun 21.

Modeling Amyotrophic Lateral Sclerosis in Pure Human iPSc-derived Motor Neurons Isolated by a Novel FACS Double Selection Technique

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Modeling Amyotrophic Lateral Sclerosis in Pure Human iPSc-derived Motor Neurons Isolated by a Novel FACS Double Selection Technique

Diana Toli et al. Neurobiol Dis. .

Abstract

Amyotrophic lateral sclerosis (ALS) is a severe and incurable neurodegenerative disease. Human motor neurons generated from induced pluripotent stem cells (iPSc) offer new perspectives for disease modeling and drug testing in ALS. In standard iPSc-derived cultures, however, the two major phenotypic alterations of ALS--degeneration of motor neuron cell bodies and axons--are often obscured by cell body clustering, extensive axon criss-crossing and presence of unwanted cell types. Here, we succeeded in isolating 100% pure and standardized human motor neurons by a novel FACS double selection based on a p75(NTR) surface epitope and an HB9::RFP lentivirus reporter. The p75(NTR)/HB9::RFP motor neurons survive and grow well without forming clusters or entangled axons, are electrically excitable, contain ALS-relevant motor neuron subtypes and form functional connections with co-cultured myotubes. Importantly, they undergo rapid and massive cell death and axon degeneration in response to mutant SOD1 astrocytes. These data demonstrate the potential of FACS-isolated human iPSc-derived motor neurons for improved disease modeling and drug testing in ALS and related motor neuron diseases.

Keywords: Amyotrophic lateral sclerosis (ALS); Axon degeneration; Cell death; Fluorescent-activated cell sorting (FACS); HB9; Induced pluripotent stem cells (iPSc); Motor neuron disease; Superoxide dismutase 1 (SOD1); p75NTR.

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