Transplantation of clinical-grade human neural stem cells reduces neuroinflammation, prolongs survival and delays disease progression in the SOD1 rats

Autor: Maria Svelto, Alberto Visioli, Daniela Celeste Profico, Laura Cajola, Massimiliano Copetti, Letizia Mazzini, Francesca Pinos, Jessica Rosati, Cristina Zalfa, Elena Binda, Laura Rota Nodari, Paola Daniele, Alessandro De Luca, Lidia De Filippis, Marina Boido, Valentina Garlatti, Angelo L. Vescovi, Daniela Ferrari, Elena Vacchi, Maurizio Gelati, Alessandro Vercelli
Přispěvatelé: Zalfa, C, Rota Nodari, L, Vacchi, E, Gelati, M, Profico, D, Boido, M, Binda, E, De Filippis, L, Copetti, M, Garlatti, V, Daniele, P, Rosati, J, De Luca, A, Pinos, F, Cajola, L, Visioli, A, Mazzini, L, Vercelli, A, Svelto, M, Vescovi, A, Ferrari, D
Rok vydání: 2019
Předmět:
Male
0301 basic medicine
Cancer Research
Pathology
medicine.medical_specialty
Cell Survival
Neurogenesis
medicine.medical_treatment
Immunology
SOD1
Kaplan-Meier Estimate
hNSCs transplantation Amyotrophic Lateral Sclerosis
transgenic animal model
terapeutic mechanisms of stem cells
differentiation mechanisms of stem cells
neural stem cells
SOD1
mechanisms of ALS progression
neuroinflammation mechanisms
Article
Rats
Sprague-Dawley
03 medical and health sciences
Cellular and Molecular Neuroscience
0302 clinical medicine
Animals
Humans
Medicine
lcsh:QH573-671
Amyotrophic lateral sclerosis
Neuroinflammation
Inflammation
Motor Neurons
Neural stem cells
Superoxide Dismutase
lcsh:Cytology
business.industry
Amyotrophic Lateral Sclerosis
BIO/13 - BIOLOGIA APPLICATA
Cell Differentiation
Immunosuppression
Cell Biology
medicine.disease
Neural stem cell
Rats
Transplantation
Disease Models
Animal
030104 developmental biology
Spinal Cord
Disease Progression
Female
Microglia
Rats
Transgenic
Stem cell
business
030217 neurology & neurosurgery
Zdroj: Cell Death and Disease, Vol 10, Iss 5, Pp 1-15 (2019)
Cell Death & Disease
ISSN: 2041-4889
DOI: 10.1038/s41419-019-1582-5
Popis: Stem cells are emerging as a therapeutic option for incurable diseases, such as Amyotrophic Lateral Sclerosis (ALS). However, critical issues are related to their origin as well as to the need to deepen our knowledge of the therapeutic actions exerted by these cells. Here, we investigate the therapeutic potential of clinical-grade human neural stem cells (hNSCs) that have been successfully used in a recently concluded phase I clinical trial for ALS patients (NCT01640067). The hNSCs were transplanted bilaterally into the anterior horns of the lumbar spinal cord (four grafts each, segments L3–L4) of superoxide dismutase 1 G93A transgenic rats (SOD1 rats) at the symptomatic stage. Controls included untreated SOD1 rats (CTRL) and those treated with HBSS (HBSS). Motor symptoms and histological hallmarks of the disease were evaluated at three progressive time points: 15 and 40 days after transplant (DAT), and end stage. Animals were treated by transient immunosuppression (for 15 days, starting at time of transplantation). Under these conditions, hNSCs integrated extensively within the cord, differentiated into neural phenotypes and migrated rostro-caudally, up to 3.77 ± 0.63 cm from the injection site. The transplanted cells delayed decreases in body weight and deterioration of motor performance in the SOD1 rats. At 40DAT, the anterior horns at L3–L4 revealed a higher density of motoneurons and fewer activated astroglial and microglial cells. Accordingly, the overall survival of transplanted rats was significantly enhanced with no rejection of hNSCs observed. We demonstrated that the beneficial effects observed after stem cell transplantation arises from multiple events that counteract several aspects of the disease, a crucial feature for multifactorial diseases, such as ALS. The combination of therapeutic approaches that target different pathogenic mechanisms of the disorder, including pharmacology, molecular therapy and cell transplantation, will increase the chances of a clinically successful therapy for ALS.
Databáze: OpenAIRE
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