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Stem Cells Pass First Trial for ALS. “Lumbar intraspinal injection of neural stem cells in patients with ALS - Results of a Phase I trial in 12 patients”

 

Amyotrophic lateral sclerosis (ALS) causes muscle weakness and atrophy throughout the body and is caused by the degeneration of motor neurons.   Stem cell therapy has been proposed as a possible treatment for ALS through cell replacement or through additional support to affected neurons (Lunn et al).   Human spinal cord-derived stem cells (HSSCs) derived from an 8-week gestation foetus (Guo et al) have shown some therapeutic benefit in rat models of ALS and ischemic spinal cord injury (SCI) (Cizkovaet al and Xu et al) and therefore suggests that they may also be applicable to stem cell therapy in humans.   Now, published in Stem Cells, the results of a successful phase I trial of intraspinal injections of fetal-derived neural stems cells (NSCs) in patients with ALS have been reported (Glass et al).

A Therapeutic Stroke in the Right Direction?

‘Implantation site and lesion topology determine efficacy of a human neural stem cell line in a rat model of chronic stroke’

From Stem Cells
Commentary by Carla B. Mellough

Stroke remains one of the leading causes of mortality and adult disability in developed nations1-3. For the survivors of stroke, the resulting disability is often persistent in nature and severely affects an individual’s quality of life, with the additional possibility of recurrent stroke events a grim reality. Over the past four decades, while the incidence of stroke has declined in high-income countries there has been a greater than 100% increase in low to middle-income countries, highlighting the magnitude of this cardiovascular problem.3 Yet strategies to maximize recovery and help improve patient outcome following stroke have made little progress, with only 3% of patients currently gaining any benefit from existing treatment strategies, such as the use of thrombolytic agents.4 There is therefore an obvious need for the development of restorative therapies which would help to address the loss of neurons and glia in the brain following stroke. For a cell-based therapeutic approach, determining the optimal cell type for use that will apply to a broad cross section of stroke patients while giving consistent results and minimal complications is key. Various cell types have been tested in experimental stroke ranging from embryonic, mesenchymal and neural stem cells to human umbilical cord blood, in addition to some less obvious candidates such as adipose and menstrual blood cells, with preclinical studies indicating varying positive outcomes but, importantly, that many different cell types can elicit encouraging results.4,5 Many of the cell types that have been tested appear to exert their effects not by cell replacement, but by their neurotrophic and anti-inflammatory effects on affected tissues, and therefore act by minimizing damage and providing protection to brain tissues. Neuronal precursors derived from human embryonic stem cells (hESCs) tested in a rat model of stroke were shown to elicit some functional recovery,6 but the application of such strategies to the clinic remain somewhat hampered by the potential tumorigenicity of any residual stem cells which may be transplanted alongside more differentiated cell types. Until measures to reduce this potentiality are optimized, human neural stem cells (hNSCs) represent a good alternative. In the current study, Smith et al.7 report on the use of a human cortical neuroepithelium-derived hNSC line (CTX0E03) which, in previous studies has shown efficacy in improving sensorimotor function in a dose-dependent manner and, unlike other hNSCs, shows limited migration capacity thereby providing a locally-acting cell based therapy which makes it potentially safer than other hNSC types. This work represents a collaborative study from Kings College London, the UK based company ReNeuron and the University of Pittsburgh in Pennsylvania.

Rejuvenation of Regeneration in the Aging Central Nervous System

From Cell Stem Cell
By Stuart P. Atkinson

Oligodendrocytes precursor cells (OPCs) differentiate into oligodendrocytes with remyelination capabilities which, in the adult central nervous system (CNS), restores conduction, prevents axonal degradation and promotes functional recovery. Reduction in this capacity in aging (Sim et al) leads to demyelinated neurons and axonal degeneration, which is understood to be mediated in part by environmental signals (Hinks and Franklin). This suggests that exogenous factors may be able to reverse this age-associated decline in function, which has now been addressed in an article (Ruckh and Zhao et al) in Cell Stem Cell by researchers in the laboratory of Amy J. Wagers (Howard Hughes Medical Institute) and Robin J.M. Franklin (MRC Centre for Stem Cell Biology and Regenerative Medicine).

The Rho Kinase Pathway Regulates Mouse Adult Neural Precursor Cell Migration

Article Focus for this Month’s Edition of Stem Cells

Paper commentary by Carla B. Mellough

The subventricular zone (SVZ) is a multicellular structure that lines the lateral walls of the lateral ventricles of the brain. SVZ ependymal cells face the ventricular lumen and are involved in the production and circulation of cerebrospinal fluid. Further, the SVZ is an established site of adult neurogenesis, boasting the largest population of proliferative cells in the brain of mature rodents, monkeys and humans. The neural precursor cells (NPCs) of the SVZ produce neuroblasts which migrate to the olfactory bulb via the rostral migratory stream (RMS). These ordinarily act to replenish olfactory neurons, however following central nervous system (CNS) damage they become capable of migrating towards ectopic sites of injury. The mobilisation and guidance of NPCs towards a distinct neural destination involves numerous external signals which must be integrated and translated by neuroblasts to produce an appropriate response, allowing specific and directed migration. The Rho-GTPase family of molecules and their related regulatory members such as the Rac and PIk3 proteins have previously been demonstrated to influence cell migration by regulating the translation of external signals into cytoskeletal reorganisation, yet their role in the migration of neuroblasts through the adult RMS had not yet been established. In the February edition of Stem Cells, new results by Leong et al. from Ann Turnley’s laboratory at the Centre for Neuroscience at The University of Melbourne, begin to reveal the role of the Rho-GTPase pathway in the migration of adult mouse SVZ NPCs.

Nutritional Signals Regulate Stem Cell Quiescence and Proliferation

It has been over ten years since the physiological link between nutritional input and growth and development in Drosophila was established, yet the mechanisms downstream of nutritional stimuli that act to regulate the growth of the organism were unknown. Results published recently in Cell from Chell and Brand at the Gurdon Institute and Department of Physiology, Development and Neuroscience at the University of Cambridge now shed light on the identity and action of these nutrition-dependent signals. Their research reveals that following nutritional stimulus neural stem cells (or neuroblasts) exit quiescence in response to the release of insulin/insulin-like growth factor (IGF)-like peptides (ILP2 and ILP6) from adjacent glial cells. The authors demonstrate that these peptides elicit their effect by means of the insulin-like receptor on glial cells and that this activates the phosphoinositide 3-kinase (PI3K)-Akt pathway. Whilst the authors noted elevated PI3K activation as neuroblasts were entering the proliferation stage, absence of the PI3K catalytic subunit maintained neuroblasts in the quiescent state. Their results provide insight into systemic control of neuroblasts by nutrition, and highlights glia as a key regulator of the stem cell niche.

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