Neural stem cell therapy for neurodegenerative disorders: The role of neurotrophic support
Introduction
The potential of cell transplantation as a therapy for neurodegenerative disorders was first examined nearly three decades ago with landmark studies of fetal mesencephalic tissue transplantation in Parkinson's disease (PD) patients (Lindvall et al., 1988). Although these initial studies produced variable results, the field's interest in this approach continued to grow and increasingly focused on the regenerative potential of neural stem cells (NSCs) in the hope that they could provide a renewable and more precise source of cells for transplantation. Building upon preclinical findings from PD models, researchers began to also investigate NSC transplantation for other neurodegenerative conditions including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD). As a result the field's understanding of NSC transplantation and the mechanisms by which they influence these disorders has grown immensely. Yet significant challenges remain regarding if and how these promising preclinical findings can be translated into successful clinical trials.
Section snippets
Are NSCs a viable therapeutic approach for neurodegenerative disorders?
Researchers initially hypothesized that NSCs could likely only be practically developed as a therapy for disorders that involve relatively focal neural degeneration. For example, PD that is characterized primarily by a loss of dopaminergic neurons within the Substantia Nigra Pars Compacta represented an excellent candidate disease in which to develop a neuronal replacement paradigm (Lotharius and Brundin, 2002, Martino and Pluchino, 2006). While the development of this approach continues to
Neurotrophic factors in CNS disorders & potential therapeutic approaches
Beginning with the discovery of the first neurotrophic factor, nerve growth factor (NGF), more than half a century ago researchers have identified approximately 50 such factors that can influence the growth, survival, and homeostatic functions of cells within the central and peripheral nervous systems (Levi-Montalcini and Hamburger, 1951, Nagahara and Tuszynski, 2011). Among the most prominently studied neurotrophic factors in the CNS are NGF, brain-derived neurotrophic factor (BDNF), glial
NSC transplantation for Alzheimer's disease
Alzheimer's disease is the most common cause of age-related neurodegeneration, affecting over 5 million people in the U.S. alone (Alzheimer’s Association, 2016). AD is characterized by a progressive loss of memory and cognition that leads to an inability to perform daily activities and eventually death (Alzheimer’s Association, 2016). Despite its prevalence and initial discovery over 100 years ago, there are still no disease modifying therapies for Alzheimer's disease and currently approved
Neurotrophins and Parkinson's disease
Parkinson's disease is a debilitating neurodegenerative disorder that is characterized by impairment in motor function. Patients often exhibit hallmark motor phenotypes consisting of tremors, slowed or excessive rigidity of movement, and difficulty initiating movements (Lotharius and Brundin, 2002). Unfortunately, up to 70% of PD patients also go on to develop Parkinson's disease dementia (PDD) during the course of the disease (Dubois and Pillon, 1997, Marsh and Blurton-Jones, 2012). While
Huntington's disease
Huntington's disease is a dominantly-inherited progressive neurodegenerative disorder that results in impairments in both cognitive and motor functions that eventually lead to death (Albin and Tagle, 1995). HD is caused by an expansion of a triplet repeat DNA sequence within the Huntington gene that leads to the production of a mutant protein containing an enlarged and pathogenic polyglutamine tract (Albin and Tagle, 1995, Maucksch et al., 2013, Group, 1993). HD symptoms typically begin around
Remaining challenges
The studies discussed in this mini-review support the conclusion that NSC-mediated delivery of neurotrophins, either through endogenous production or overexpression, could provide a viable approach to treat many neurodegenerative disorders. However, there remain important questions and limitations that need to be addressed before this approach can be translated toward clinical trials. One of the greatest challenges when attempting to integrate the work of many different groups into the
Conclusions
Taken together the studies discussed in this review have begun to provide insight into the efficacy of NSC transplantation as a potential therapy for a variety of neurodegenerative disorders. Many studies of NSC transplantation initially focused on replacement of dead or dying cells, however, a growing body of work has now shown that NSC-mediated regulation of neurotrophic support likely provides many additional and important benefits. While there are still many challenges and questions that
Author contributions
S.E.M and M.B-J wrote the paper.
Conflicts of interest
No conflicts of interest to declare.
Acknowledgements
S.E.M. and M.B-J. have received research funding from NIH RF1AG048099 (M.B-J.), NIH P50 AG016573 (M.B-J.), the Alzheimer's Association BFG-14-317000 (M.B-J.), California Institute for Regenerative Medicine RT3-07893 (M.B-J.), NIA T32 AG00096-30 (S.E.M.), and NINDS T32 NS082174-01 (S.E.M.).
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