A cutting-edge strategy for spinal cord injury treatment: resident cellular transdifferentiation

Abstract

Spinal cord injury causes varying degrees of motor and sensory function loss. However, there are no effective treatments for spinal cord repair following an injury. Moreover, significant preclinical advances in bioengineering and regenerative medicine have not yet been translated into effective clinical therapies. The spinal cord's poor regenerative capacity makes repairing damaged and lost neurons a critical treatment step. Reprogramming-based neuronal transdifferentiation has recently shown great potential in repair and plasticity, as it can convert mature somatic cells into functional neurons for spinal cord injury repair in vitro and in vivo, effectively halting the progression of spinal cord injury and promoting functional improvement. However, the mechanisms of the neuronal transdifferentiation and the induced neuronal subtypes are not yet well understood. This review analyzes the mechanisms of resident cellular transdifferentiation based on a review of the relevant recent literature, describes different molecular approaches to obtain different neuronal subtypes, discusses the current challenges and improvement methods, and provides new ideas for exploring therapeutic approaches for spinal cord injury.

Keywords: direct reprogramming; nerve repair; neurons; spinal cord injury; transdifferentiation.

FIGURE 1

The molecular mechanism underlying neuronal transdifferentiation. This figure summarizes how transcription factors (TFs), microRNAs (miRNAs), and five small molecules acting in vivo induce astrocyte fate switching; the outcome is the direct transdifferentiation of astrocytes into neurons. Precursor TFs increase the accessibility of otherwise silenced target genes, making them key hubs for the three classes of actors. TFs and miRNAs act as endogenous factors to induce the overexpression of precursor factors through ex vivo pathways, activating the transcription of neuronal programs. Small molecules can also play a role in inducing transdifferentiation through transcription factor-mediated pathways; however, the mode of action of small molecules is more likely to promote neuronal fate through signaling pathways such as Wnt, ROCK, and cyclic AMP-protein kinase A.

FIGURE 2

In vivo protocol for the induction of specific neuronal subtypes. (A) This figure summarizes the aspects to be considered in transdifferentiation protocols that describe the top-down pathway for generating specific neuronal subtypes. The main drivers and reinforcing factors act as public players in most approaches, primarily inhibiting non-neuronal fates and cellular transformation to pan-neuronal fates. Meanwhile, different brain regions and subtype specification factors further formulate specific functional neuronal subtypes. (B) Examples of experiments that induce different neuronal subtypes in vivo mentioned in this review.

FIGURE 3

Effect of neuronal transdifferentiation strategies occurring in the injured spinal cord. This figure depicts the transdifferentiation of astrocytes to functional neurons in the injured spinal cord induced by external injection intervention at the macroscopic level with three substances or different combinations of them. The effects of this strategy for the injured spinal cord include the reconstruction of neural circuits, reversal of scar tissue, promotion of myelin regeneration, and alleviation of inflammation, with the ultimate result of promoting the recovery of spinal cord function.