Abstract
BackgroundSignificant developments in stem cell therapy for Parkinson’s disease (PD) have already been achieved; however, methods for reliable assessment of dopamine neuron maturation in vivo are lacking. Establishing the efficacy of new cellular therapies using non-invasive methodologies will be critical for future regulatory approval and application. The current study examines the utility of neuroimaging to characterise the in vivo maturation, innervation and functional dopamine release of transplanted human embryonic stem cell-derived midbrain dopaminergic neurons (hESC-mDAs) in a preclinical model of PD.MethodsFemale NIH RNu rats received a unilateral stereotaxic injection of 6-OHDA into the left medial forebrain bundle to create the PD lesion. hESC-mDA cell and sham transplantations were carried out 1 month post-lesion, with treated animals receiving approximately 4 × 105 cells per transplantation. Behavioural analysis, [18F]FBCTT and [18F]fallypride microPET/CT, was conducted at 1, 3 and 6 months post-transplantation and compared with histological characterisation at 6 months.ResultsPET imaging revealed transplant survival and maturation into functional dopaminergic neurons. [18F]FBCTT-PET/CT dopamine transporter (DAT) imaging demonstrated pre-synaptic restoration and [18F]fallypride-PET/CT indicated functional dopamine release, whilst amphetamine-induced rotation showed significant behavioural recovery. Moreover, histology revealed that the grafted cells matured differently in vivo producing high- and low-tyrosine hydroxylase (TH) expressing cohorts, and only [18F]FBCTT uptake was well correlated with differentiation.ConclusionsThis study provides further evidence for the value of in vivo functional imaging for the assessment of cell therapies and highlights the utility of DAT imaging for the determination of early post-transplant cell maturation and differentiation of hESC-mDAs.
Highlights
Significant developments in stem cell therapy for Parkinson’s disease (PD) have already been achieved; methods for reliable assessment of dopamine neuron maturation in vivo are lacking
This study provides further evidence for the value of in vivo functional imaging for the assessment of cell therapies and highlights the utility of dopamine transporter (DAT) imaging for the determination of early post-transplant cell maturation and differentiation of human embryonic stem cells (hESCs)-midbrain dopaminergic neurons (mDAs)
Results from transplantation studies have shown that transplants with high levels of A9-like dopaminergic neurons are most likely to lead to long-term functional reinnervation [6,7,8,9,10], so the majority of studies have concentrated on midbrain dopaminergic neurons differentiated from human embryonic stem cells [11], induced pluripotent stem cells and mesenchymal stem cells (MSCs) [12,13,14]. iPSCs and hESCderived mDAs have been shown to successfully restore function the denervated striatum in preclinical rat and primate models using standard neuroimaging, behavioural and histological measures [14, 15]
Summary
Significant developments in stem cell therapy for Parkinson’s disease (PD) have already been achieved; methods for reliable assessment of dopamine neuron maturation in vivo are lacking. The current study examines the utility of neuroimaging to characterise the in vivo maturation, innervation and functional dopamine release of transplanted human embryonic stem cellderived midbrain dopaminergic neurons (hESC-mDAs) in a preclinical model of PD. IPSCs and hESCderived mDAs have been shown to successfully restore function the denervated striatum in preclinical rat and primate models using standard neuroimaging, behavioural and histological measures [14, 15] The success of such preclinical studies has led to the use of cell therapies for clinical trials; more rigorous preclinical studies are still needed to optimise graft maturation and therapeutic efficacy in vivo. Examples include [18F]FDOPA which measures the biosynthesis of dopamine, [11C]raclopride and [18F]fallypride which are capable of assessing dopamine release and tropane-derived ligands such as [18F]FP-β-CIT, [18F]FE-PE2I and [18F]FBCTT that have been developed as clinical and preclinical PET radiopharmaceuticals for the quantification of presynaptic dopamine transporter (DAT) expression [16,17,18,19]
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
