iPSC-Derived neural stem cells act via kinase inhibition to exert neuroprotective effects in spinal muscular atrophy with respiratory distress type 1

Stem Cell Reports. 2014 Aug 12;3(2):297-311. doi: 10.1016/j.stemcr.2014.06.004. Epub 2014 Jul 4.

Abstract

Spinal muscular atrophy with respiratory distress type 1 (SMARD1) is a motor neuron disease caused by mutations in the IGHMBP2 gene, without a cure. Here, we demonstrate that neural stem cells (NSCs) from human-induced pluripotent stem cells (iPSCs) have therapeutic potential in the context of SMARD1. We show that upon transplantation NSCs can appropriately engraft and differentiate in the spinal cord of SMARD1 animals, ameliorating their phenotype, by protecting their endogenous motor neurons. To evaluate the effect of NSCs in the context of human disease, we generated human SMARD1-iPSCs motor neurons that had a significantly reduced survival and axon length. Notably, the coculture with NSCs ameliorate these disease features, an effect attributable to the production of neurotrophic factors and their dual inhibition of GSK-3 and HGK kinases. Our data support the role of iPSC as SMARD1 disease model and their translational potential for therapies in motor neuron disorders.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Axons / metabolism
  • Cell Differentiation
  • Cell Lineage
  • Coculture Techniques
  • Disease Models, Animal
  • Glycogen Synthase Kinase 3 / antagonists & inhibitors
  • Glycogen Synthase Kinase 3 / metabolism
  • Humans
  • Induced Pluripotent Stem Cells / cytology*
  • Kaplan-Meier Estimate
  • Mice
  • Motor Neurons / cytology
  • Motor Neurons / metabolism
  • Muscular Atrophy, Spinal / mortality
  • Muscular Atrophy, Spinal / therapy
  • Nerve Growth Factors / metabolism
  • Neural Stem Cells / cytology*
  • Neural Stem Cells / transplantation
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors
  • Protein-Serine-Threonine Kinases / metabolism*
  • Respiratory Distress Syndrome, Newborn / mortality
  • Respiratory Distress Syndrome, Newborn / therapy
  • Transplantation, Heterologous

Substances

  • Nerve Growth Factors
  • Protein-Serine-Threonine Kinases
  • Glycogen Synthase Kinase 3

Supplementary concepts

  • Spinal muscular atrophy with respiratory distress 1