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Title: Adipose derived stem cells for cell therapy of amyotrophic lateral sclerosis
Author: Ciervo, Yuri
ISNI:       0000 0004 8506 3018
Awarding Body: University of Sheffield
Current Institution: University of Sheffield
Date of Award: 2019
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Amyotrophic Lateral Sclerosis (ALS) is a devastating neurodegenerative condition characterised by progressive motor neuron loss leading to paralysis and ultimately death. Because of the complexity and high heterogeneity of the disease, single drugs have failed as effective therapeutic options and new therapies are urgently needed. Cell-based therapy is a promising therapeutic strategy in ALS. Given their immunomodulation properties and the capacity to secrete neuroprotective factors, adipose derived stem cells (ADSCs) represent an excellent candidate for clinical application. It is hypothesised that intrathecal injection of ADSCs may be beneficial in ALS, because of the capacity of these cells to modulate the toxic microenvironment that leads to motor neuronal degeneration. The therapeutic potential of mouse derived ADSCs is first investigated by injecting GFP+ -ADSCs into the cerebrospinal fluid of transgenic SOD1G93A ALS mice. ADSCs persisted for 4 weeks and were unable to migrate into the spinal cord parenchyma. Despite these limitations, ADSCs improved motor function and delayed disease onset in SOD1G93A mice compared to vehicle-injected animals. Pathological analysis in the spinal cord showed that ADSCs attenuated motor neuron (MN) death and reduced glial activation. The neuroprotective potential of ADSCs was then evaluated in vitro, in astrocyte/MN co-cultures where astrocytes show toxicity. Through the secretion of soluble factors, ADSCs protected MNs from both astrocytes derived from symptomatic SOD1G93A mice, and from human iAstrocytes obtained by reprogramming fibroblasts from patients with either sporadic or familial ALS. Further, ADSCs displayed the capacity to reduce the inflammatory phenotype of SOD1G93A astrocytes by inhibiting the release of pro-inflammatory mediators and inducing the secretion of neuroprotective factors. In conclusion, our data in two translational models of disease show that through paracrine mechanisms ADSCs support MN survival and modulate the toxic microenvironment that contributes to neurodegeneration, indicating these cells as potential candidates for the development of a cell-based therapy in ALS.
Supervisor: Shaw, Pamela ; Mead, Richard ; Ning, Ke ; Xu, Jun Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available