Neural stem cell transplantation can ameliorate the phenotype of a mouse model of spinal muscular atrophy
Stefania Corti, Monica Nizzardo, Martina Nardini, Chiara Donadoni, Sabrina Salani, Dario Ronchi, Francesca Saladino, Andreina Bordoni, Francesco Fortunato, Roberto Del Bo, Dimitra Papadimitriou, Federica Locatelli, Giorgia Menozzi, Sandra Strazzer, Nereo Bresolin, Giacomo P. Comi
Stefania Corti, Monica Nizzardo, Martina Nardini, Chiara Donadoni, Sabrina Salani, Dario Ronchi, Francesca Saladino, Andreina Bordoni, Francesco Fortunato, Roberto Del Bo, Dimitra Papadimitriou, Federica Locatelli, Giorgia Menozzi, Sandra Strazzer, Nereo Bresolin, Giacomo P. Comi
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Research Article Neuroscience

Neural stem cell transplantation can ameliorate the phenotype of a mouse model of spinal muscular atrophy

Abstract

Spinal muscular atrophy (SMA), a motor neuron disease (MND) and one of the most common genetic causes of infant mortality, currently has no cure. Patients with SMA exhibit muscle weakness and hypotonia. Stem cell transplantation is a potential therapeutic strategy for SMA and other MNDs. In this study, we isolated spinal cord neural stem cells (NSCs) from mice expressing green fluorescent protein only in motor neurons and assessed their therapeutic effects on the phenotype of SMA mice. Intrathecally grafted NSCs migrated into the parenchyma and generated a small proportion of motor neurons. Treated SMA mice exhibited improved neuromuscular function, increased life span, and improved motor unit pathology. Global gene expression analysis of laser-capture-microdissected motor neurons from treated mice showed that the major effect of NSC transplantation was modification of the SMA phenotype toward the wild-type pattern, including changes in RNA metabolism proteins, cell cycle proteins, and actin-binding proteins. NSC transplantation positively affected the SMA disease phenotype, indicating that transplantation of NSCs may be a possible treatment for SMA.

Authors

Stefania Corti, Monica Nizzardo, Martina Nardini, Chiara Donadoni, Sabrina Salani, Dario Ronchi, Francesca Saladino, Andreina Bordoni, Francesco Fortunato, Roberto Del Bo, Dimitra Papadimitriou, Federica Locatelli, Giorgia Menozzi, Sandra Strazzer, Nereo Bresolin, Giacomo P. Comi

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Figure 6

NSC transplantation ameliorates muscle innervation in SMA mice.

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NSC transplantation ameliorates muscle innervation in SMA mice. SMA mice...
SMA mice were treated with vehicle (n = 6) or NSCs (n = 6), and WT littermates were treated with vehicle (n = 6) on days P1. (A–C) H&E-stained cross sections of TA muscle. (D–F) Histograms of myofiber diameters. (G) Mean TA muscle cross-sectional area was reduced in SMA mice compared with WT littermates and increased after NSC transplantation (**P < 0.00001). Data represent mean values ± SD. (H) Mean TA muscle total myofiber number was reduced in SMA mice compared with WT littermates and increased after NSC treatment (†P < 0.00001). (I–K) Immunofluorescence analysis of NMJs was performed within the gastrocnemii of SMA mice treated with NSCs (I) or vehicle (J) or of WT littermates (P13) (K). α-Bungarotoxin was used to label AChR (red). (L) Histogram showing the mean NMJ diameter in treated and untreated SMA and wild-type gastrocnemii at P13, demonstrating an increased size in treated mice (**P < 0.00001, treated versus untreated SMA; †P < 0.00001, SMA versus WT). Scale bar: 300 μm (A–C); 10 μm (I–K).