Amyotrophic lateral sclerosis (ALS) is a fatal incurable neurodegenerative disease characterized by progressive degeneration of motor neurons (MNs), leading to relentless muscle paralysis. In the early stage of the disease, MN loss and consequent muscle denervation are compensated by axonal sprouting and reinnervation by the remaining MNs, but this mechanism is insufficient in the long term. Here, we demonstrate that induced pluripotent stem cell (iPSC)-derived neural stem cells (NSCs), in particular the subpopulation positive for LewisX-CXCR4-β1-integrin, enhance neuronal survival and axonal growth of human ALS-derived MNs co-cultured with toxic ALS astrocytes, acting on both autonomous and non-autonomous ALS disease features. Transplantation of this NSC fraction into transgenic SOD1G93A ALS mice protects MNs in vivo, promoting their ability to maintain neuromuscular junction integrity, inducing novel axonal sprouting and reducing macro- and microgliosis. These effects result in a significant increase in survival and an improved neuromuscular phenotype in transplanted SOD1G93A mice. Our findings suggest that effective protection of MN functional innervation can be achieved by modulation of multiple dysregulated cellular and molecular pathways in both MNs and glial cells. These pathways must be considered in designing therapeutic strategies for ALS patients.

iPSC-derived LewisX+CXCR4+β1-integrin+ neural stem cells improve the amyotrophic lateral sclerosis phenotype by preserving motor neurons and muscle innervation in human and rodent models / M. Nizzardo, M. Bucchia, A. Ramirez, E. Trombetta, N. Bresolin, G.P. Comi, S. Corti. - In: HUMAN MOLECULAR GENETICS. - ISSN 0964-6906. - (2016). [Epub ahead of print] [10.1093/hmg/ddw163]

iPSC-derived LewisX+CXCR4+β1-integrin+ neural stem cells improve the amyotrophic lateral sclerosis phenotype by preserving motor neurons and muscle innervation in human and rodent models

M. Nizzardo
Primo
;
M. Bucchia
Secondo
;
A. Ramirez;N. Bresolin;G.P. Comi
Penultimo
;
S. Corti
Ultimo
2016

Abstract

Amyotrophic lateral sclerosis (ALS) is a fatal incurable neurodegenerative disease characterized by progressive degeneration of motor neurons (MNs), leading to relentless muscle paralysis. In the early stage of the disease, MN loss and consequent muscle denervation are compensated by axonal sprouting and reinnervation by the remaining MNs, but this mechanism is insufficient in the long term. Here, we demonstrate that induced pluripotent stem cell (iPSC)-derived neural stem cells (NSCs), in particular the subpopulation positive for LewisX-CXCR4-β1-integrin, enhance neuronal survival and axonal growth of human ALS-derived MNs co-cultured with toxic ALS astrocytes, acting on both autonomous and non-autonomous ALS disease features. Transplantation of this NSC fraction into transgenic SOD1G93A ALS mice protects MNs in vivo, promoting their ability to maintain neuromuscular junction integrity, inducing novel axonal sprouting and reducing macro- and microgliosis. These effects result in a significant increase in survival and an improved neuromuscular phenotype in transplanted SOD1G93A mice. Our findings suggest that effective protection of MN functional innervation can be achieved by modulation of multiple dysregulated cellular and molecular pathways in both MNs and glial cells. These pathways must be considered in designing therapeutic strategies for ALS patients.
Settore MED/26 - Neurologia
Settore BIO/18 - Genetica
Settore MED/03 - Genetica Medica
6-giu-2016
Centro Dino Ferrari per la Diagnosi e la Terapia delle Malattie Neuromuscolari e Neurodegenerative
Article (author)
File in questo prodotto:
File Dimensione Formato  
hmg.ddw163.full. my AIR.pdf

accesso riservato

Tipologia: Post-print, accepted manuscript ecc. (versione accettata dall'editore)
Dimensione 1.34 MB
Formato Adobe PDF
1.34 MB Adobe PDF   Visualizza/Apri   Richiedi una copia
Hum. Mol. Genet.-2016-Nizzardo-hmg-ddw163.pdf

accesso riservato

Tipologia: Publisher's version/PDF
Dimensione 1.8 MB
Formato Adobe PDF
1.8 MB Adobe PDF   Visualizza/Apri   Richiedi una copia
Pubblicazioni consigliate

Caricamento pubblicazioni consigliate

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2434/398117
Citazioni
  • ???jsp.display-item.citation.pmc??? 7
  • Scopus 20
  • ???jsp.display-item.citation.isi??? 18
social impact