Cell Reprogramming for Regeneration and Repair of the Nervous System

Abstract

A persistent barrier to the cure and treatment of neurological diseases is the limited ability of the central and peripheral nervous systems to undergo neuroregeneration and repair. Recent efforts have turned to regeneration of various cell types through cellular reprogramming of native cells as a promising therapy to replenish lost or diminished cell populations in various neurological diseases. This review provides an in-depth analysis of the current viral vectors, genes of interest, and target cellular populations that have been studied, as well as the challenges and future directions of these novel therapies. Furthermore, the mechanisms by which cellular reprogramming could be optimized as treatment in neurological diseases and a review of the most recent cellular reprogramming in vitro and in vivo studies will also be discussed.

Keywords: cell-reprograming; gene therapies; neuro-regeneration.

Figure 1

In vivo cell reprogramming. Current research into cell reprogramming has focused on translating the approach to in vivo models of neurological disorders to determine the extent of nervous system repair. (a) Reprogramming factors are commonly administered to target cell populations through viral transduction. Viral vectors loaded with the reprogramming transcription factor controlled under a target cell-specific promoter is injected into the site of reprogramming interest to induce in vivo cell reprogramming in transduced target cells. (b) One significant benefit to cell reprogramming as a therapeutic approach is its adaptability toward targeting various neurological disorders for nervous system restoration. Cell damage and loss is a common pathology across several neurological disorders where in vivo reprogramming would serve to replenish lost cell populations and recover cell function. (c) Functional recovery remains a significant outcome measure of successful in vivo reprogramming in animal models of neurological disorders where animals would hypothetically display functional improvements in behavioral assays.

Figure 2

Current strategies to induce cell reprogramming. Methodologies used to reprogram cells in vitro and in vivo include the use of viral transduction, small molecule cocktails, or CRISPR-based gene editing to force expression of neurogenic transcription factors in the target cell populations. Viral-based reprogramming commonly makes use of cell-specific promoters and Cre-lox technology to target specific cell populations for reprogramming. Small molecule cocktails are engineered to upregulate cell signaling pathways involved in neurodifferentiation. CRISPR technology has been used to target cells for specific expression of transcription factors. These transcription factors—such as NeuroD1, Ascl1, Dxl2, Brn2, and Neurog2—are selected as key factors involved in cells differentiating into neurons.

Figure 3

In vitro cell reprogramming. Several cell populations have been identified as targets capable of cell fate reprogramming when cultured with specific reprogramming factors. (a) Published literature on in vitro cell reprogramming have targeted astrocytes, microglia, pericytes, and fibroblasts, among others, as candidate cell populations targeted for reprogramming. To achieve cell reprogramming, the targeted cells are cultured with particular transcription factors designed to change the cell fate into a cell of interest. (b) This process is commonly designed to generate induced neurons. As such, targeted cells are cultured with proneural transcription factors significant to neurodevelopment. Following administration of proneural factors via small molecule cocktail or viral transduction, target cells are selectively reprogrammed into functional neurons and neuron-like cells.