Significant 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. Female 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. PET 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. This 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.

中文翻译：

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多巴胺转运蛋白神经成像可在帕金森氏病的临床前模型中准确评估多巴胺神经元的成熟。

帕金森氏病（PD）干细胞治疗的重要进展已经实现；然而，缺乏可靠的评估体内多巴胺神经元成熟的方法。使用非侵入性方法建立新的细胞疗法的功效对于将来的法规批准和应用至关重要。当前的研究检查了神经影像学在PD的临床前模型中表征移植的人胚胎干细胞衍生的中脑多巴胺能神经元（hESC-mDAs）体内成熟，神经支配和功能性多巴胺释放的作用。雌性NIH RNu大鼠接受单侧立体定向注射6-OHDA到左内侧前脑束中，形成PD病变。病变后1个月进行hESC-mDA细胞和假移植，接受处理的动物每次移植接受约4×105个细胞。在移植后1、3和6个月进行行为分析，即[18F] FBCTT和[18F]氟利肽microPET / CT，并与6个月时的组织学特征进行比较。PET成像显示移植存活和成熟为功能性多巴胺能神经元。[18F] FBCTT-PET / CT多巴胺转运蛋白（DAT）成像显示突触前恢复，[18F] Falpride-PET / CT显示功能性多巴胺释放，而苯丙胺诱导的旋转显示出明显的行为恢复。此外，组织学表明移植的细胞在体内成熟不同，产生高和低酪氨酸羟化酶（TH）表达队列，只有[18F] FBCTT摄取与分化密切相关。