Parkinson's disease is characterised by the loss of dopaminergic (DA) neurons, which arise from ventral midbrain neural progenitors. Therapeutically functional cell types can be generated from human pluripotent stem cells (hPSCs) by activating Wnt signalling, which is vital in anterior-posterior patterning during neural development. Current hPSC protocols target GSK3, a kinase involved in Wnt and other signalling pathways. Here, Stephane Angers and colleagues leverage selective antibodies against Frizzled (FZD) receptors of the Wnt pathway, which they previously developed, to stimulate midbrain progenitor differentiation in hPSCs. First, the authors observe that FZD5 is upregulated in anterior neural progenitors, and its expression is downregulated as the progenitors adopt a posterior fate. Then, they find that a FZD5-selective antibody (F5L6.13) can trigger midbrain progenitor differentiation and give rise to functional DA neurons in vitro. DA neurons derived using this protocol can rescue motor dysfunction when engrafted into rodent models of Parkinson’s disease. Finally, the authors find that although F5L6.13 and a GSK3 inhibitor are equally efficient at directing progenitors toward the DA cell fate, a subpopulation of DA neurons generated by F5L6.13 aligns more closely with the anatomical origin of DA neurons. Overall, the findings show that specifically activating Wnt pathway by targeting FZD5 can promote midbrain patterning for improved hPSC neuronal differentiation.
