number of issues may still limit the promise of this approach. As noted, past trials of fetal human midbrain tissue implanted into the striata of Parkinson’s patients yielded inconsistent results, with durable efficacy in selected cases (Kefalopoulou et al., 2014), yet many others that failed or developed refractory dyskinesias. While improved dopaminergic cell purity and acquisition of midbrain nigral phenotype have been achieved in vitro, whether a new generation of studies using these more homogeneous cell preparations will translate into more consistently improved clinical outcomes remains unknown. At the very least, PSC-derived dopaminergic populations appear as efficacious as their tissue-derived counterparts in rodent models of Parkinson’s Disease (Grealish et al., 2014). Nonetheless, the striatal site of implantation remains fundamentally heterotopic, such that putatively nigral dopaminergic donor cells are deprived of their normal afferents, and are instead engaged by cortical, intrastriatal and thalamic afferents that they would otherwise never encounter. Regardless of donor cell phenotype, it thus remains unclear – even after two decades of study in this field - whether the fundamentally non-physiological circuitry that results from intrastriatal dopaminergic engraftment is sufficiently malleable to restore normal basal ganglia function to Parkinson’s patients.
