Transplantation of an iPSC-derived CD15+CXCR4+VLA4+ neural stem cell subpopulation as a new therapy for ALS. (I8-1A)

OBJECTIVE: The aim of the study was the identification of a novel specific subset of Neural Stem Cells (NSCs) as a potential therapy for the Amyotrophic Lateral Sclerosis (ALS) mouse model. BACKGROUND: ALS is a progressive neurodegenerative disease characterized by unremitting loss of upper and lower motor neurons of the Central Nervous System (CNS). No effective therapies are presently available. We recently showed that transplantation of NSCs, differentiated from human induced pluripotent stem cells (iPSCs),into a mouse model of ALS can ameliorate their neurodegenerative phenotype (Nizzardo et al., 2014). Here, we expand on these data through the study of a novel specific subset of NSCs that displays enhanced migratory features. DESIGN/METHODS: We obtained iPSCs from healthy human skin fibroblasts using a non-viral episomal method and we differentiated them in NSCs. Preliminary injections were performed in pups in order to optimize the protocol of injection. By FACS selection we isolated a specific NSC subpopulation based on positivity for CD15+CXCR4+VLA4+. The phenotype of these cells was assessed by morphologic, gene expression, and protein profile analyses. iPSC-purified NSCs were administered by intrathecal injections into ALS mice (SOD1G93A mice) and neuropathological assays and functional tests were performed to evaluate any modifications of disease hallmarks. RESULTS: CD15+CXCR4+VLA4+NSCs showed their capacity to proliferate and differentiate into the three neuroectodermal lineages, both in vitro and in vivo. We analyzed their capacity to migrate into the CNS after minimally invasive injection, and to engraft into the host spinal cord. Transplanted NSCs migrated into the CNS and differentiated into the three neuroectodermal lineages. CONCLUSIONS: We demonstrated that iPSC-derived NSC transplantation significantly enhanced survival of endogenous motor neurons, by reducing macrogliosis. These data suggest that the specific selection of NSC subsets can contribute to the development of new therapeutic cell-mediated approaches for ALS. Study Supported by: ALS association Disclosure: Dr. Simone has nothing to disclose. Dr. Nizzardo has nothing to disclose. Dr. Rizzo has nothing to disclose. Dr. Bucchia has nothing to disclose. Dr. Ramirez has nothing to disclose. Dr. Bresolin has nothing to disclose. Dr. Comi has nothing to disclose. Dr. Corti has nothing to disclose.