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Exp Neurol. 2019 Nov;321:113041. doi: 10.1016/j.expneurol.2019.113041. Epub 2019 Aug 21.

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.

Author information

1
Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.
2
Dino Ferrari Centre, Neuroscience Section, Department of Pathophysiology and Transplantation (DEPT), University of Milan, Italy.
3
Flow Cytometry Service, Analysis Laboratory, Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.
4
Center for Surgical Research, Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.
5
Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy; Dino Ferrari Centre, Neuroscience Section, Department of Pathophysiology and Transplantation (DEPT), University of Milan, Italy.
6
Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy; Dino Ferrari Centre, Neuroscience Section, Department of Pathophysiology and Transplantation (DEPT), University of Milan, Italy. Electronic address: stefania.corti@unimi.it.

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.

KEYWORDS:

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

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