Direct Neuronal Reprogramming for Disease Modeling Studies Using Patient-Derived Neurons: What Have We Learned?

Abstract

Direct neuronal reprogramming, by which a neuron is formed via direct conversion from a somatic cell without going through a pluripotent intermediate stage, allows for the possibility of generating patient-derived neurons. A unique feature of these so-called induced neurons (iNs) is the potential to maintain aging and epigenetic signatures of the donor, which is critical given that many diseases of the CNS are age related. Here, we review the published literature on the work that has been undertaken using iNs to model human brain disorders. Furthermore, as disease-modeling studies using this direct neuronal reprogramming approach are becoming more widely adopted, it is important to assess the criteria that are used to characterize the iNs, especially in relation to the extent to which they are mature adult neurons. In particular: i) what constitutes an iN cell, ii) which stages of conversion offer the earliest/optimal time to assess features that are specific to neurons and/or a disorder and iii) whether generating subtype-specific iNs is critical to the disease-related features that iNs express. Finally, we discuss the range of potential biomedical applications that can be explored using patient-specific models of neurological disorders with iNs, and the challenges that will need to be overcome in order to realize these applications.

A Quantitative Model of Cellular Decision Making in Direct Neuronal Reprogramming

“…Our analysis did not predict that the conversion strategy based on PTB knockdown would result in cells with a neuron-like identity, but instead showed an increase in nPTB expression without affecting other genes. Interestingly, although PTB knockdown has been used successfully in a number of conversion experiments 16,30 , this negative experimental outcome has also been observed in the lab 22 . We provide a speculative but plausible explanation for this variation in results by observing that, in our best model, the conversion was blocked by constitutive activation of REST.…”

Dual modulation of neuron‐specific microRNAs and the REST complex promotes functional maturation of human adult induced neurons

“…Induced neurons can be used for disease modeling, diagnostics, and drug screening [2,30,31]. As the technology becomes more and more refined, the use of iNs to model neurological diseases is increasing.…”

Induced pluripotent stem cell‐based modeling of mutant LRRK2‐associated Parkinson's disease

“…Besides transcriptomic signatures, iN preserve the donor cell's age-associated epigenetic memory and other aging hallmarks such as shortened telomere lengths, elevated ROS levels and accumulated DNA damage (Huh et al, 2016). Thus, it is not surprising that iNs have also entered the arena of disease modeling (reviewed by Drouin-Ouellet, Pircs, Barker, Jakobsson, & Parmar, 2017). As a recent example, Huntington's disease (HD) patient fibroblasts converted into induced medium spiny neurons (iMSNs) were found to exhibit multifaceted mitochondrial dysfunctions, leading to oxidative DNA damage and spontaneous cell death (Victor et al, 2018).…”