Modeling Hypoxia-Induced Neuropathies Using a Fast and Scalable Human Motor Neuron Differentiation System

Stem Cell Reports. 2020 Jun 9;14(6):1033-1043. doi: 10.1016/j.stemcr.2020.04.003. Epub 2020 May 7.


Human motor neuron (MN) diseases encompass a spectrum of disorders. A critical barrier to dissecting disease mechanisms is the lack of appropriate human MN models. Here, we describe a scalable, suspension-based differentiation system to generate functional human MN diseases in 3 weeks. Using this model, we translated recent findings that mRNA mis-localization plays a role in disease development to the human context by establishing a membrane-based system that allows efficient fractionation of MN cell soma and neurites. In response to hypoxia, used to mimic diabetic neuropathies, MNs upregulated mitochondrial transcripts in neurites; however, mitochondria were decreased. These data suggest that hypoxia may disrupt translation of mitochondrial mRNA, potentially leading to neurite damage and development of neuropathies. We report the development of a novel human MN model system to investigate mechanisms of disease affecting soma and/or neurites that facilitates the rapid generation and testing of patient-specific MN diseases.

Keywords: cell compartments; diabetic neuropathies; fractionation; hypoxia; neurites; soma; stem cell-derived human motor neurons.

Publication types

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

MeSH terms

  • Action Potentials
  • Cell Hypoxia
  • Cell Line
  • Cells, Cultured
  • Diabetic Neuropathies / metabolism*
  • Humans
  • Induced Pluripotent Stem Cells / cytology
  • Mitochondria / metabolism
  • Mitochondrial Proteins / genetics
  • Mitochondrial Proteins / metabolism
  • Motor Neurons / cytology*
  • Motor Neurons / metabolism
  • Motor Neurons / physiology
  • Neuronal Outgrowth*
  • Oxygen / metabolism*
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism


  • Mitochondrial Proteins
  • RNA, Messenger
  • Oxygen