Progress and Challenges of Cell Replacement Therapy for Neurodegenerative Diseases Based on Direct Neural Reprogramming

Neurodegenerative diseases are characterized by protein aggregation and progressive degeneration of neurons, causing severe functional deficiency in cognition, behavior, and movement. Until now, there has been no effective treatment available in the clinic. Considering the selective loss of specific neurons in the human brain in the pathogenesis of these diseases, generating functional neurons in vitro or in vivo to replace the lost neurons represents a novel strategy to treat neurodegenerative diseases. Human embryonic stem cells and induced pluripotent stem cells have good potential for cell replacement therapy. However, limitations, such as the possibility of tumor formation, have hindered its applications. Recently, a novel approach, direct neural reprogramming, in which somatic cells are reprogrammed to functional neurons without a stem-cell state, has emerged an alternative for cell replacement. Specific human somatic cells can be reprogrammed to functional subtype neurons via the introduction of transcription factors, microRNAs, or small molecules in vitro and in vivo, thereby reducing the risk of carcinogenesis. Studies demonstrated symptomatic relief when induced neurons were transplanted into animal models. Although the direct neural reprogramming holds great promise for cell replacement therapy, there remain a number of challenges for its clinical application, including low efficiency, unclear mechanisms, and safety concerns. This review highlights the progress and challenges of this technique, and discusses perspectives for its applications in cell replacement.