Derivation of dopaminergic neurons from pluripotent stem cells

Midbrain dopamine neurons play a critical role in motor function and in reward-related motivational behaviors. The goal of developing a renewable source of human midbrain dopamine neurons was prompted by the pioneering studies on the use of human fetal dopamine neurons as an experimental therapy for the treatment of Parkinson's disease. More recently, dopamine neurons have also turned into an important tool for modeling of Parkinson's disease in patient-specific induced pluripotent stem cell lines. Protocols for the directed differentiation of mouse ESCs into midbrain dopamine neurons have been developed more than a decade ago and the successful derivation of human midbrain dopamine neurons was reported soon after. However, the initial human ESC reports were unable to demonstrate efficient in vivo dopamine neuron engraftment. Only very recently, those challenges have been overcome by using an alternative differentiation strategy that is based on deriving midbrain dopamine neurons via a distinct midbrain floor plate intermediate. With those novel tools in hand, it should now become possible to test the full potential of midbrain dopamine neurons in regenerative medicine and human disease modeling. However, several challenges remain such as the need to develop strategies that can enrich for selective subtypes of midbrain dopamine neurons, techniques to control postmitotic dopamine neuron maturation, and finally, clinical grade differentiation protocols that enable the production dopamine neurons suitable for human cell therapy.