Transplantation of Neural Precursors Derived from Induced Pluripotent Cells Preserve Perineuronal Nets and Stimulate Neural Plasticity in ALS Rats

Int J Mol Sci. 2020 Dec 16;21(24):9593. doi: 10.3390/ijms21249593.

Abstract

A promising therapeutic strategy for amyotrophic lateral sclerosis (ALS) treatment is stem cell therapy. Neural progenitors derived from induced pluripotent cells (NP-iPS) might rescue or replace dying motoneurons (MNs). However, the mechanisms responsible for the beneficial effect are not fully understood. The aim here was to investigate the mechanism by studying the effect of intraspinally injected NP-iPS into asymptomatic and early symptomatic superoxide dismutase (SOD)1G93A transgenic rats. Prior to transplantation, NP-iPS were characterized in vitro for their ability to differentiate into a neuronal phenotype. Motor functions were tested in all animals, and the tissue was analyzed by immunohistochemistry, qPCR, and Western blot. NP-iPS transplantation significantly preserved MNs, slowed disease progression, and extended the survival of all treated animals. The dysregulation of spinal chondroitin sulfate proteoglycans was observed in SOD1G93A rats at the terminal stage. NP-iPS application led to normalized host genes expression (versican, has-1, tenascin-R, ngf, igf-1, bdnf, bax, bcl-2, and casp-3) and the protection of perineuronal nets around the preserved MNs. In the host spinal cord, transplanted cells remained as progenitors, many in contact with MNs, but they did not differentiate. The findings suggest that NP-iPS demonstrate neuroprotective properties by regulating local gene expression and regulate plasticity by modulating the central nervous system (CNS) extracellular matrix such as perineuronal nets (PNNs).

Keywords: ALS; iPS; motoneuron death; neurodegeneration; plasticity; proteoglycans; stem cells; transplantation.

MeSH terms

  • Amyotrophic Lateral Sclerosis / therapy*
  • Animals
  • Apoptosis Regulatory Proteins / genetics
  • Apoptosis Regulatory Proteins / metabolism
  • Cells, Cultured
  • Humans
  • Induced Pluripotent Stem Cells / cytology
  • Male
  • Nerve Growth Factors / genetics
  • Nerve Growth Factors / metabolism
  • Nerve Regeneration
  • Neural Stem Cells / cytology
  • Neural Stem Cells / metabolism
  • Neural Stem Cells / transplantation*
  • Neuronal Plasticity*
  • Peripheral Nerves / physiology
  • Rats
  • Rats, Sprague-Dawley
  • Stem Cell Transplantation / methods*
  • Tenascin / genetics
  • Tenascin / metabolism
  • Versicans / genetics
  • Versicans / metabolism

Substances

  • Apoptosis Regulatory Proteins
  • Nerve Growth Factors
  • Tenascin
  • Versicans