Neuronal replacement: Concepts, achievements, and call for caution.

Regenerative approaches have made such a great progress, now aiming toward replacing the exact neurons lost upon injury or neurodegeneration. Transplantation and direct reprogramming approaches benefit from identification of molecular programs for neuronal subtype specification, allowing engineering of more precise neuronal subtypes. Disentangling subtype diversity from dynamic transcriptional states presents a challenge now. Adequate identity and connectivity is a prerequisite to restore neuronal network function, which is achieved by transplanted neurons generating the correct output and input, depending on the location and injury condition. Direct neuronal reprogramming of local glial cells has also made great progress in achieving high efficiency of conversion, with adequate output connectivity now aiming toward the goal of replacing neurons in a noninvasive approach.