CSF transplantation of a specific iPSC-derived neural stem cell subpopulation ameliorates the disease phenotype in a mouse model of spinal muscular atrophy with respiratory distress type 1

Giulia Forotti, Monica Nizzardo, Monica Bucchia, Agnese Ramirez, Elena Trombetta, Stefano Gatti, Nereo Bresolin, Giacomo Pietro Comi, Stefania Corti

Research output: Contribution to journalArticlepeer-review

Abstract

Spinal muscular atrophy with respiratory distress type 1 (SMARD1) is a genetic motor neuron disease affecting infants. This condition is caused by mutations in the IGHMBP2 gene and currently has no cure. Stem cell transplantation is a potential therapeutic strategy for motor neuron diseases such as SMARD1, exerting beneficial effects both by replacing cells and by providing support to endogenous motor neurons. In this work, we demonstrate that human induced pluripotent stem cell (iPSC)-derived neural stem cells (NSCs) selected for the expression of specific markers, namely, Lewis X, CXCR4 and beta 1 integrin, and pretreated with neurotrophic factors and apoptosis/necroptosis inhibitors were able to effectively migrate and engraft into the host parenchyma after administration into the cerebrospinal fluid in a SMARD1 mouse model. We were able to detect donor cells in the ventral horn of the spinal cord and observe improvements in neuropathological features, particularly preservation of the integrity of the motor unit, that were correlated with amelioration of the SMARD1 disease phenotype in terms of neuromuscular function and lifespan. This minimally invasive stem cell approach can confer major advantages in the context of cell-mediated therapy for patients with neurodegenerative diseases.

Original languageEnglish
Article number113041
JournalExperimental Neurology
Volume321
DOIs
Publication statusPublished - Nov 1 2019

Keywords

  • Neural stem cells
  • Spinal muscular atrophy with respiratory distress type 1
  • Transplantation

ASJC Scopus subject areas

  • Neurology
  • Developmental Neuroscience

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