Abstract
Evidence from carefully conducted open label clinical trials suggested that therapeutic benefit can be achieved by grafting fetal dopaminergic (DAergic) neurons derived from ventral mesencephalon (VM) into the denervated striatum of Parkinson's disease (PD) patients. However, two double-blind trials generated negative results reporting deleterious side effects such as prominent dyskinesias. Heterogeneous composition of VM grafts is likely to account for suboptimal clinical efficacy.We consider that gene expression patterns of the VM tissue needs to be better understood by comparing the genetic signature of the surviving and functioning grafts with the cell suspensions used for transplantation. In addition, it is crucial to assess whether the grafted cells exhibit the DAergic phenotype of adult substantia nigra pars compacta (SNpc). To investigate this further, we used a GFP reporter mouse as source of VM tissue that enabled the detection and dissection of the grafts 6 weeks post implantation. A comparative gene expression analysis of the VM cell suspension and grafts revealed that VM grafts continue to differentiate post-implantation. In addition, implanted grafts showed a mature SNpc-like molecular DAergic phenotype with similar expression levels of TH, Vmat2 and Dat. However, by comparing gene expression of the adult SNpc with dissected grafts we detected a higher expression of progenitor markers in the grafts. Finally, when compared to the VM cell suspension, post-grafting there was a higher expression of markers inherent to glia and other neuronal populations.In summary, our data highlight the dynamic development of distinctive DAergic and non-DAergic gene expression markers associated with the maturation of VM grafts in vivo. The molecular signature of VM grafts and its functional relevance should be further explored in future studies aimed at the optimization of DAergic cell therapy approaches in PD.
Highlights
Parkinson’s disease (PD) is a neurodegenerative disorder characterized by a progressive loss of dopaminergic (DAergic) neurons of the substantia nigra pars compacta (SNpc) with a subsequent reduction in striatal dopamine content accounting for parkinsonian features such as bradykinesia, rigidity and tremor at rest [1]
Owing to the different tissue preparations between studies, it is likely that the large variation in the outcome between patients is in part associated with the lack of standardization and quality control requirements for ventral mesencephalic (VM) grafts [34,35]
In order to advance our understanding of the molecular and cellular changes occurring in embryonic VM grafts in vivo, we analyzed their molecular signature prior to and six weeks post-grafting in the unilateral 6OHDA rat model
Summary
Parkinson’s disease (PD) is a neurodegenerative disorder characterized by a progressive loss of dopaminergic (DAergic) neurons of the substantia nigra pars compacta (SNpc) with a subsequent reduction in striatal dopamine content accounting for parkinsonian features such as bradykinesia, rigidity and tremor at rest [1]. Studies in animal models of PD provide the proof of principle of DAergic cell therapy showing that grafted DAergic neurons reinnervate the denervated striatum and make synaptic contact, release dopamine, receive inputs from host neurons and improve motor deficits [4]. These experiments led to a series of open label clinical trials demonstrating meaningful and sustained clinical benefit derived from DAergic rich fetal ventral mesencephalic (VM) grafts [5]. In patients transplanted with fetal mesencephalon that developed GID after some years of exhibiting major motor recovery, GID were correlated with a hyperinnervation of the host striatum by 5-HT neurons [13]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
