Development-Inspired Reprogramming of the Mammalian Central Nervous System

Background: Differentiated cells can be reprogrammed to switch identities from one cell type to another under the direction of powerful transcription factors. In the mammalian central nervous system, this approach has been used experimentally to generate new categories of neuronal cells. The protocols are inspired by what we have learned from normal development, but the applications lie outside of normal embryogenesis. The research is changing how scientists think about regeneration of lost neurons and modeling of neuronal function in the central nervous system. The approaches also allow for new ways to study human neuronal development, a process that cannot be studied in vivo.Advances: Neurons are a highly specialized cell type, with their ability to transmit electrical signals. Beyond that, though, neurons also specialize into an astonishing diversity of classes. Although reprogramming with known transcription factors is a comparatively blunt tool, researchers have used knowledge of normal neuronal development to identify suites of factors that can convert mouse or human non-neuronal cells into induced neuronal cells showing class-specific features. These protocols have provided a renewable source of neuronal cells for high-throughput studies, which is particularly useful when source tissue is rare or unavailable. One exciting application of lineage reprogramming has been the generation of new neurons in situ by the direct conversion of other cell types already resident within the brain. Astrocytes have been converted into neurons in vivo. Even neurons have been changed from one subtype to another in young animals, indicating that postmitotic neurons may not be as immutable as once thought. These provocative results may foster the development of strategies for neuronal replacement that rely on “code-switching” of neuronal identity on the spot.Outlook: Direct lineage reprogramming is a nascent but promising field. Although both unspecialized and specialized neuronal cells have already been generated by these methods, we still need more refined understanding of how reprogramming works, how the cellular context constrains reprogramming routes, and what synergistic effects arise with various reprogramming factors. Better-defined criteria are needed to classify neurons obtained by reprogramming and to determine how they differ from their endogenous counterparts. Functional analyses are also necessary to clarify when a new neuron achieves the needed function, even if its other features do not match endogenous neurons. The challenge requires collaborative expertise in stem cell biology, embryology, and fundamental neuroscience. Future ability to reprogram postmitotic neurons in the adult brain will be important for the growth of this field and likely influence the way we think about neuronal stability, regeneration, and function. Repairing the Brain Research with stem cells and reprogramming of cellular fates is leading to improved understanding of neurodevelopmental events, as well as opening doors to possible cellular replacement therapies. Amamoto and Arlotta (10.1126/science.1239882) review recent progress in this field and highlight the discoveries made and the remaining challenges as stem-cell technologies are applied to cells of the central nervous system. In 2012, John Gurdon and Shinya Yamanaka shared the Nobel Prize for the demonstration that the identity of differentiated cells is not irreversibly determined but can be changed back to a pluripotent state under appropriate instructive signals. The principle that differentiated cells can revert to an embryonic state and even be converted directly from one cell type into another not only turns fundamental principles of development on their heads but also has profound implications for regenerative medicine. Replacement of diseased tissue with newly reprogrammed cells and modeling of human disease are concrete opportunities. Here, we focus on the central nervous system to consider whether and how reprogramming of cell identity may affect regeneration and modeling of a system historically considered immutable and hardwired.