Neural stem cell transplantation can ameliorate the phenotype of a mouse model of spinal muscular atrophy
Stefania Corti, … , Nereo Bresolin, Giacomo P. Comi
Stefania Corti, … , Nereo Bresolin, Giacomo P. Comi
Published September 2, 2008
Citation Information: J Clin Invest. 2008;118(10):3316-3330. https://doi.org/10.1172/JCI35432.
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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 3

NSC transplantation extends survival, attenuates weight loss, and improves the motor behavior of SMA mice.

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NSC transplantation extends survival, attenuates weight loss, and improv...
SMA mice were treated with intrathecal injections of ALDHhiSSClo stem cells or vehicle on day P1. (A) Photographs showing the gross appearance of an NSC-treated SMA mouse (SMA Tr), an untreated SMA mouse (SMA), and a WT mouse. The treated SMA mice were larger than the untreated mice. (B) Kaplan-Meier survival curves of SMA mice treated with “primed” NSCs (SMA Tr), undifferentiated ALDHhiSSClo cells (SMA NSC), ALDHhiSSClo-derived astrocytes (SMA Astro), and primary fibroblasts (SMA Fibro) or untreated mice (SMA; n = 24 for each group). Survival was significantly extended for mice transplanted with primed NSCs compared with undifferentiated NSCs (P = 0.002, log-rank test); astrocytes and fibroblasts (P < 0.00001); or vehicle (P < 0.00001, log-rank test). (C) Weight curves of SMA ALDHhiSSClo treated mice (n = 24) or untreated (n = 24) and unaffected littermate WT controls (n = 24). All plots show means of weight at each day, with error bars representing SD. Treated SMA mice displayed an increased growth rate with respect to untreated SMA mice (10–13 days; P < 0.00001). (D) Grip time in treated SMA mice (n = 24) or untreated SMA (n = 24) and unaffected littermate WT controls (n = 24). The grip time was statistically different in the untreated and treated SMA mice (P < 0.00001) at 12–13 days of age. Error bars represent SD.