Abstract
Understanding of cell-type specific transcription factors has promoted progress in methods for cellular reprogramming, such as directly reprogramming somatic cells to induced neurons (iN). Methods for direct reprogramming require neuronal-fate determining gene activation via neuron-specific microRNAs, chemical modulation of key neuronal signaling pathways or overexpression via viral vectors, with some reprogramming strategies requiring a combination of these methods to induce the neuronal-cell fate. These methods have been employed in a multitude of cell types, including fibroblasts, hepatocytes, peripheral blood mononuclear, and T cells. The ability to create iN from skin biopsies and blood samples coupled with recent advancements in artificially inducing age- and disease-associated phenotypes are accelerating the development of disease models for late-onset neurodegenerative disorders. Here, we review how activation of the neuronal transcriptome alters the epigenetic landscape of the donor cell to facilitate reprogramming to neurons. We also discuss the advantages of using DNA binding domains such as CRISPR/dCas9 to overcome epigenetic barriers to induce neuronal-cell fate by activating endogenous neuronal cell-fate determining genes.
Highlights
The ability to model human disease in vitro was transformed by the reprogramming of somatic cells into induced pluripotent stem cells with defined factors (Takahashi and Yamanaka, 2006; Takahashi et al, 2007). This breakthrough was followed by the differentiation of iPSCs into the neuronal lineage which outlined master regulators and signal transduction pathways involved in establishing a neuronal phenotype in vitro (Figure 1) (Chambers et al, 2009; Karumbayaram et al, 2009; Cooper et al, 2010)
Inhibiting telomerase activity in iPSCs recapitulated ageassociated phenotypes such as DNA damage and reactive oxygen induced neurons (iN) and Outs of Reprogramming to Induced Neurons species levels following differentiation to dopaminergic neurons (Vera et al, 2016). While these studies have primarily been validated in iPSC-derived neurons, the results suggest that artificially inducing age in vitro is possible
The mechanisms underlying reprogramming are diverse and comprehensive analysis is required to determine if current methods are sufficient to recapitulate the epigenomic and transcriptomic signatures observed during neurogenesis
Summary
The ability to model human disease in vitro was transformed by the reprogramming of somatic cells into induced pluripotent stem cells (iPSCs) with defined factors (Takahashi and Yamanaka, 2006; Takahashi et al, 2007) This breakthrough was followed by the differentiation of iPSCs into the neuronal lineage which outlined master regulators and signal transduction pathways involved in establishing a neuronal phenotype in vitro (Figure 1) (Chambers et al, 2009; Karumbayaram et al, 2009; Cooper et al, 2010). Constitutive expression of pluripotent reprogramming factors can lead to karyotypic instability and prevents differentiation of iPSCs to the neuronal lineage (Ramos-Mejia et al, 2010; Ramos-Mejía et al, 2012) These findings present a potential limitation for iPSC-derived neurons to mature and exhibit key pathologies of age-related neurodegenerative disorders, while highlighting the importance of establishing tools for neuronal reprogramming which delineate developmental and pathological milestones in vitro. Direct reprogramming to neuronal cells requires activation of neuronal-fate determining genes, chemical modulation of key neuronal signaling pathways, overexpression via viral vectors, or endogenous activation using DNA binding domains (Table 1)
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