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.

SMN deficiency in severe models of spinal muscular atrophy causes widespread intron retention and DNA damage

“…Several previous studies, including ours, have reported strong up-regulation of Cdkn1a/p21, a cyclin-dependent kinase inhibitor and mediator of cell cycle arrest downstream of p53, as well as other regulators of cell cycle and DNA repair in SMA models (6,19,(23)(24)(25). Whereas the Cdkn1a up-regulation has been attributed to a p53-independent stabilization of Cdkn1a transcript in the absence of SMN protein (26,27), few other gene expression changes can be explained by such posttranscriptional regulation.…”

Concise Review: Aldehyde Dehydrogenase Bright Stem and Progenitor Cell Populations from Normal Tissues: Characteristics, Activities, and Emerging Uses in Regenerative Medicine

“…ALDHbr cells were cultured under conditions that promoted formation of motor neurons and transplanted i.t. into mouse models of spinal motor atrophy [48,49]. Both transplanted neurons and uncultured ALDHbr cells migrated to ventral horns and established functional neuromuscular junctions.…”

“…Uncultured, freshly isolated ALDHbr cells also improved the disease progression and secreted several of protective cytokines, although not as much as the cultured cells. Corti et al [49] suggested that isolating ALDHbr cells and culturing them in the absence of the inhibitory effects of spinal cord glial cells promotes the development of cells that can produce neuroprotective cytokines. This recalls the effect of enriching ALDHbr cells on efficacy of human bone marrow in the hind limb ischemia model discussed above.…”

Stem Cell Therapy: In Treatment of Neurodegenerative Diseases

“…Cellular therapies, however, have been examined in mouse models of SMA, where grafting of ES derived NPCs protected MNs from degeneration and improved survival. 37 The correction of SMN gene, using singlestranded oligonucleotide, was shown to restore the SMN gene profile in neurons derived from SMA-iPSC, converting SMN2 in SMN1. 38 It is possible that for SMA, transient rescue of the developmental loss of SMN may be sufficient to confer efficacy, which may not be the case for other neurodegenerative diseases where long-term degeneration of the transplanted cells is a valid concern.…”