LAUSR

Parkinson disease (PD) is a leading neurodegenerative disorder that affects more than 1% of the population aged 65 and above (de Rijk et al., 2000). With a growing aging population globally, more effective therapeutic regimes are needed. Neuropathological hallmarks of PD include the presence of Lewy bodies (protein aggregates mainly composed of a-synuclein) and progressive loss of dopaminergic neurons located in the substantia nigra. Cell-restorative regenerative therapy such as dopaminergic neuron transplantation therefore represents a potentially promising remedy for PD. Pioneering works in the 1980s used primarily catecholamine-producing adrenal medullary (AM) tissues and fetal ventral mesencephalon (fVM) (Backlund et al., 1985; Lindvall et al., 1989, 1990; Madrazo et al., 1987). It was soon realized that while transplants of AM produced little efficacy in patients, they caused significant unintended side effects. The lack of major clinical improvement, together with poor graft survival based on postmortem analyses, cast doubts on this approach (Jankovic et al., 1989). Preclinical animal studies using transplants of human fVM, on the other hand, showed more encouraging results (Clarke, Dunnett, Isacson, Sirinathsinghji, & Bj€ orklund, 1988; Dunnett, Isacson, Sirinathsinghji, Clarke, & Bj€ orklund, 1988). Consistent with the positive outcomes from animal models, human clinical trials using fVM produced significant motor improvement in the majority of the patients receiving the grafts (Wenning et al., 1997). Although overall clinical improvements are variable, both in strength and in duration, the fact that several individuals did enjoy long-term benefits (more than 20 years) with robust graft survival and target tissue reinnervation endorses this tissue type as a viable option for cell transplantation (Kefalopoulou et al., 2014; Li et al., 2016), and spawned subsequent clinical trials including the ongoing TRANSEURO. Despite these promising results, human fVM transplants suffer from several limitations that prevent the procedure from being widely used. The scarcity of suitable fetal tissue and ethical concerns are just two such barriers. The successful derivation of human embryonic stem cells (hESCs) in 1998 opened a new prospect of generating desired dopaminergic neurons for transplantation (Thomson et al., 1998). Subsequent years have witnessed a myriad of protocols being developed to guide the stem cells to tyrosine hydroxylase–expressing (TH) dopaminergic neurons, culminating in the generation of “authentic” A9-like DA neurons capable of tonic firing (Kirkeby et al., 2012; Kriks et al., 2011). In a series of preclinical animal models, these cells have been demonstrated to survive, integrate, innervate, and functionally rescue motor phenotypes of the animals with similar potency and efficacy compared with fetal tissue (Grealish et al., 2014). These experiments paved the way for clinical trials using these carefully differentiated cells, yet issues concerning ethics and immune rejection remain. More recently, clinical trials in humans have identified troubling dyskinesias in transplanted patients and a lack of efficacy in some patients despite postmortem evidence of reinnervation (Kordower et al., 2017). The recent discovery of pluripotent stem cells induced from somatic cells (iPSCs) bypasses the above-mentioned two issues and opens up the possibility of autologous transplants (Takahashi et al., 2007). The molecular profile and differentiation capacity of iPSCs have been demonstrated to be essentially equivalent to those of hESCs. Many labs have leveraged this approach to model PD, mostly focusing on characterizing the in vitro abnormal cellular phenotypes using dopaminergic neurons derived from PD iPSCs carrying the rare PD-causing genes (such as LRRK2) (Bahmad et al., 2017; Nguyen et al., 2011). Fewer studies have examined idiopathic PDs, which account for the vast majority of PD. However, to use these cells in the clinical cell replacement setting for PD, critical parameters including graft survival, reinnervation, and motor function rescue must be rigorously evaluated in preclinical animal models. In addition, it is unclear whether PD iPSC-derived neurons would be intrinsically more vulnerable to cell death, and whether these cells are more susceptible to pathological a-synuclein transmission once transplanted into the patients. To address these important issues, Kikuchi and Takahashi et al. differentiated a panel of idiopathic PD iPSCs and healthy control iPCSs to midbrain dopaminergic neurons, and characterized any differences both in vitro and in vivo after transplantation into rodent brains (Kikuchi et al., 2017). They reported that PD iPSC-derived neurons are not more vulnerable when compared with cells from healthy subjects upon in vitro challenges with neurotoxins such as rotenone and MPP1. Upon transplantation into 6-OHDA lesioned rats, a widely used PD animal model, PD iPSC-derived neurons rescued abnormal contralateral rotations just as well as the healthy cells did. Consistent with the motor behavior recovery, a similar number of grafted cells survived and expressed TH between PD patients and healthy donors. Lastly, the authors transplanted these cells into a-synuclein transgenic