Insights and applications of direct neuronal reprogramming

Abstract

Direct neuronal reprogramming converts somatic cells of a defined lineage into induced neuronal cells without going through a pluripotent intermediate. This approach not only provides access to the otherwise largely inaccessible cells of the brain for neuronal disease modeling, but also holds great promise for ultimately enabling neuronal cell replacement without the use of transplantation. To improve efficiency and specificity of direct neuronal reprogramming, much of the current efforts aim to understand the mechanisms that safeguard cell identities and how the reprogramming cells overcome the barriers resisting fate changes. Here, we review recent discoveries into the mechanisms by which the donor cell program is silenced, and new cell identities are established. We also discuss advancements that have been made toward fine-tuning the output of these reprogramming systems to generate specific types of neuronal cells. Finally, we highlight the benefit of using direct neuronal reprogramming to study age-related disorders and the potential of in vivo direct reprogramming in regenerative medicine.

Figure 1.

Direct neuronal reprogramming. (A) Various combinations of lineage-determining neuronal transcription factors allow for generation of specific neuronal sub-population. (B) Direct reprogramming in vivo aims to develop treatments and neuronal replacement strategies in situ by converting resident brain cells into neurons, while the in vitro applications represent the widely used today approaches for disease modeling ‘in a dish’. In this regard, direct reprogramming of somatic cell types, i.e., fibroblasts, into neurons has unique advantage over reprograming involving pluripotent stem cells during modeling of age-related disorders, as it preserves age-specific epigenetic signatures of the donor cells. (C) Mechanistically, successful cell fate transition during reprogramming involves activation of the neuronal gene expression and concomitant silencing of the alternate cell fates, including the donor gene expression programs (created with BioRender.com).