Abstract
In vivo cell reprogramming of glial cells offers a promising way to generate new neurons in the adult mammalian nervous system. This approach might compensate for neuronal loss occurring in neurological disorders, but clinically viable tools are needed to advance this strategy from bench to bedside. Recently published work has described the successful neuronal conversion of glial cells through the repression of a single gene, polypyrimidine tract-binding protein 1 (Ptbp1), which encodes a key RNA-binding protein. Newly converted neurons not only express correct markers but they also functionally integrate into endogenous brain circuits and modify disease symptoms in in vivo models of neurodegenerative diseases. However, doubts about the nature of “converted” neurons, in particular in vivo, have been raised, based on concerns about tracking reporter genes in converted cells. More robust lineage tracing is needed to draw definitive conclusions about the reliability of this strategy. In vivo reprogramming and the possibility of implementing it with approaches that could be translated into the clinic with antisense oligonucleotides targeting a single gene like Ptbp1 are hot topics. They warrant further investigation with stringent methods and criteria of evaluation for the ultimate treatment of neurological diseases.
Highlights
Neurodegenerative diseases are disabling and often fatal disorders characterized by the progressive loss of specific neuronal subpopulations in various parts of the nervous system and specific profiles of neurological dysfunction.Neurons in the human central nervous system (CNS) are not normally replaced through adult neurogenesis once they are lost, aside from a negligible fraction [1,2,3]
The discovery that PTB reduction in glial cells can reprogram them into neurons began from the seminal observation of this phenomenon in murine and human fibroblasts, followed by the investigation of the transdifferentiation mechanisms via a PTB-miRNA
The evolutionary differences between human and mouse are reflected in the different regulatory mechanisms of PTB/neural PTB (nPTB)-mediated loops [17], and undoubtedly, translation to humans is still limited by the moderate efficiency of reprogramming, by possible cellular mistargeting, and by potential side effects caused by local astrocyte depletion
Summary
Neurodegenerative diseases are disabling and often fatal disorders characterized by the progressive loss of specific neuronal subpopulations in various parts of the nervous system and specific profiles of neurological dysfunction. RNA-seq analyses and quantitative RT-PCR on PTB-depleted MEF cells were instrumental in identifying a spectrum of up- or downregulated genes involved in neuronal differentiation, such as the TFs Ascl, Brn, and Myt1l [30], as well as NeuroD1, which is known to enhance neurogenesis in human fibroblasts [31], and miR-124 and miR-9, which sustain TFs during the neurogenic process [32]. Neuronal Reprogramming of Human Cells Is Mediated by the Sequential Activation of Two. Given the reproducibility of the PTB/miR-124/REST loop induced by PTB knockdown and the high conservation of this pathway in mammals, Xue and colleagues further explored a molecular strategy to induce reprogramming in two lines of human adult fibroblasts (HAFs) [34]. Overturning these gatekeepers enables the deterministic reprogramming of human fibroblasts into functional neurons
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