Download Cellular and Molecular Aspects of Cell Therapy in Mouse Models of Parkinson's Disease and Traumatic Brain Injury Book in PDF, Epub and Kindle
Neurodegenerative diseases such as Parkinson's disease (PD) and traumatic brain injuries (TBI) are the most common causes of neural cell death and constitute a serious public health concern with hundreds of thousand people affected each year. In this way, many efforts are developed to understand the molecular and cellular bases of neurodegenerative processes and to devise effective therapies. Indeed, several surgery- or drug-based treatments have been postulated as therapeutic avenues for TBI and PD. For example, deep brain stimulation aims to relieve symptomatic complications in patients with PD and decompressive craniectomy can reduce the intracranial pressure after TBI. Pharmaceutical interventions in TBI include drugs that target secondary injury mechanisms. In PD, using dopamine agonists such as L-DOPA aims to compensate the dopaminergic (DA) loss in the striatum. However, these treatments are most often symptomatologic and do not completely re-establish the degenerated pathways or lost neurons. In this way, cell therapy is a promising avenue to restore disrupted pathways and replace lost neurons in PD and TBI. In this work, we studied molecular and cellular mechanisms of a cell therapy in mouse models of PD and TBI.In PD, fetal cell transplantations have been long considered as a promising therapeutic approach to restore the disrupted nigrostriatal dopaminergic connectivity which is initially established under the influence of multiple axon guidance cues. We and others previously showed that intranigral transplantation in adult mice model of PD, of fetal ventral mesencephalon cells collected from E12.5 mice embryos functionally and anatomically restores the motor deficits. In addition, we previously showed that Semaphorin7A (Sema7A) axon guidance molecule may be more particularly involved in this restoration since its expression increases after transplantation in several regions surrounding the nigrostriatal pathway. By this mean, we investigated the influence of Sema7A on the nigrostriatal pathway reconstruction in a mouse model of PD, toxically induced with 6-hydroxydopamine and after grafting with E12.5 ventral mesencephalon fetal cells. We also tested the influence of this axon guidance molecule in the establishment of this pathway during embryogenesis and in intact adult brain using Sema7A knock-out mice. We showed that Sema7A is necessary for the development of the DA neurons in the ventral mesencephalon during embryogenesis and is differentially expressed in the adult striatum, suggesting its implication in the mesostriatal DA topography. After fetal cell therapy in a mouse model of PD, we showed that Sema7A may play a role in the neuroinflammation processes described to decrease the survival of the grafted cells. These results bring new insights on the role of Sema7A in the development of DA neurons and for protective strategies of grafted cells in cell therapy approaches. Finally, we explored the whole proteome in nigrostriatal pathway-related regions in adults to test the influence of fetal cell transplantation on protein expression.Cortical brain injuries are also candidates for cell replacement strategies to ameliorate functional recovery and anatomical repair. Thus, as presented in the second part of this work, we assessed the effects of neural cell transplantation in a mild controlled cortical impact mouse model of TBI. We observed that implantation of embryonic neural stem cells or of differentiated cells decreases neuroinflammation and enhances neurogenesis following grafting. Moreover, association of neural stem cell transplantation with docosahexaenoic acid injections significantly attenuated TBI-induced motor function deficits and promoted neurogenesis.In conclusion, considering a combined therapeutic strategy by integrating cell transplantation protocols and targeting specific molecules involved in normal functioning of the neuronal circuitry, could ameliorate recovery in patients with PD and TBI.