Development-inspired reprogramming of the mammalian central nervous system

Abstract

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.

Figure 1. Historical perspective on nuclear reprogramming

Selected milestone findings from experiments in amphibians first demonstrated that the nucleus of 16-cell stage cells(63) and differentiated adult cells(2) are plastic and capable of generating full organisms. Conrad Waddington is credited for theoretically conceiving the epigenetic landscape(8). More recent evidence indicates that differentiated mammalian cells are equally able to reprogram to either a pluripotent state(6, 64) or to a new differentiated cell state(65).

Figure 2. Direct reprogramming of various cell types into induced neuronal cells in vitro

(A) Cultured pericytes (20), (B) astrocytes (–18), (C) hepatocytes (19), and (D) fibroblasts (22, 23) are reprogrammed into induced neurons by defined factors. (E) Fibroblasts are reprogrammed into iDA neurons (38, 39) and (F) iMNs (34). Here, we illustrate selected methods for the direct conversion into these neuronal subtypes. Blue box = mouse reprogramming factors. Red box = human reprogramming factors.

Figure 3. Historical perspective on neuronal reprogramming and reprogramming into neurons

Selected milestone experiments that collectively supported the view that neurons are amenable to be reprogrammed and that non-neuronal cell types can be reprogrammed into neurons. Neurons could be generated from non-neuronal cells in vitro (15), and successive studies have shown that lineage-distant fibroblasts could be used as the starting cells for direct reprogramming into generic neurons (22) and specific neuronal subtypes (34, 38). Somatic cell nuclear transfer experiments have determined that adult neurons can undergo nuclear reprogramming (51, 52). Studies have induced neuronal class-switch in vivo (–60), suggesting that some neurons can undergo lineage reprogramming, although this capacity drastically decreases with neuronal age.

Figure 4. In vivo direct reprogramming of various cell types into neurons

(A) Endogenous callosal projection neurons of early postnatal mice are directly reprogrammed into corticofugal projection neurons (58). (B) Layer IV spiny neurons are reprogrammed into neurons with electrophysiological properties of corticofugal neurons (59). (C) Adult striatal astroctyes are reprogrammed into induced neuronal cells by overexpression of the BAM factors (48). (D) Cortical OLIG2⁺ glial cells give rise to neuronal cells upon injury combined with either inhibition of Olig2 or overexpression of Pax6 (47).