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1.
Cell Death Dis ; 10(5): 345, 2019 04 25.
Article in English | MEDLINE | ID: mdl-31024007

ABSTRACT

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.


Subject(s)
Amyotrophic Lateral Sclerosis/pathology , Neural Stem Cells/transplantation , Superoxide Dismutase/metabolism , Amyotrophic Lateral Sclerosis/mortality , Amyotrophic Lateral Sclerosis/therapy , Animals , Cell Differentiation , Cell Survival , Disease Models, Animal , Disease Progression , Female , Humans , Inflammation/metabolism , Inflammation/pathology , Kaplan-Meier Estimate , Male , Microglia/cytology , Microglia/metabolism , Motor Neurons/metabolism , Neural Stem Cells/cytology , Neural Stem Cells/metabolism , Neurogenesis , Rats , Rats, Sprague-Dawley , Rats, Transgenic , Spinal Cord/pathology , Superoxide Dismutase/genetics
2.
Cell Death Dis ; 9(10): 937, 2018 09 17.
Article in English | MEDLINE | ID: mdl-30224709

ABSTRACT

Establishing specific cell lineages from human induced pluripotent stem cells (hiPSCs) is vital for cell therapy approaches in regenerative medicine, particularly for neurodegenerative disorders. While neural precursors have been induced from hiPSCs, the establishment of hiPSC-derived human neural stem cells (hiNSCs), with characteristics that match foetal hNSCs and abide by cGMP standards, thus allowing clinical applications, has not been described. We generated hiNSCs by a virus-free technique, whose properties recapitulate those of the clinical-grade hNSCs successfully used in an Amyotrophic Lateral Sclerosis (ALS) phase I clinical trial. Ex vivo, hiNSCs critically depend on exogenous mitogens for stable self-renewal and amplification and spontaneously differentiate into astrocytes, oligodendrocytes and neurons upon their removal. In the brain of immunodeficient mice, hiNSCs engraft and differentiate into neurons and glia, without tumour formation. These findings now warrant the establishment of clinical-grade, autologous and continuous hiNSC lines for clinical trials in neurological diseases such as Huntington's, Parkinson's and Alzheimer's, among others.


Subject(s)
Cell- and Tissue-Based Therapy/methods , Induced Pluripotent Stem Cells/cytology , Neural Stem Cells/cytology , Adult , Animals , Cell Culture Techniques , Cell Differentiation/physiology , Female , Humans , Induced Pluripotent Stem Cells/metabolism , Mice, SCID , Middle Aged , Neural Stem Cells/metabolism , Neurodegenerative Diseases , Neuroglia/cytology , Neuroglia/metabolism , Neurons/cytology , Neurons/metabolism , Stem Cell Transplantation
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