In vivo glial trans‐differentiation for neuronal replacement and functional recovery in central nervous system

Abstract

The adult mammalian central nervous system (CNS) is deficient in intrinsic machineries to replace neurons lost in injuries or progressive degeneration. Various types of these neurons constitute neural circuitries wired to support vital sensory, motor, and cognitive functions. Based on the pioneer studies in cell lineage conversion, one promising strategy is to convert in vivo glial cells into neural progenitors or directly into neurons that can be eventually rewired for functional recovery. We first briefly summarize the well‐studied regeneration‐capable CNS in the zebrafish, focusing on their postinjury spontaneous reprogramming of the retinal Müller glia (MG). We then compare the signaling transductions, and transcriptional and epigenetic regulations in the zebrafish MGs with their mammalian counterparts, which perpetuate certain barriers against proliferation and neurogenesis and thus fail in MG‐to‐progenitor conversion. Next, we discuss emerging evidence from mouse studies, in which the in vivo glia‐to‐neuron conversion could be achieved with sequential or one‐step genetic manipulations, such as the conversions from retinal MGs to interneurons, photoreceptors, or retinal ganglion cells (RGCs), as well as the conversions from midbrain astrocytes to dopaminergic or GABAergic neurons. Some of these in vivo studies showed considerable coverage of subtypes in the newly induced neurons and partial reestablishment in neural circuits and functions. Importantly, we would like to point out some crucial technical concerns that need to be addressed to convincingly show successful glia‐to‐neuron conversion. Finally, we present challenges and future directions in the field for better neural function recovery.

Repressing PTBP1 is incapable to convert reactive astrocytes to dopaminergic neurons in a mouse model of Parkinson’s disease

“…The copyright holder for this this version posted November 15, 2021. ; https://doi.org/10.1101/2021.11.12.468309 doi: bioRxiv preprint PTB repression fails to convert reactive astrocytes to dopaminergic neurons in a PD model 3 tracing strategy, these two outstanding works soon aroused widespread debate and argument (Arenas, 2020;Jiang et al, 2021;Qian et al, 2021). Most recently, by adopting stringent lineage tracing method, two studies arguing against previous findings were published (Blackshaw et al, 2021;Wang et al, 2021).…”

“…Nevertheless, without substantiating the exact origin of the nascent iDAns using reliable lineage tracing strategy, these two outstanding works soon aroused widespread debate and argument (Arenas, 2020; Jiang et al, 2021; Qian et al, 2021). Most recently, by adopting stringent lineage tracing method, two studies arguing against previous findings were published(Blackshaw et al, 2021; Wang et al, 2021).…”

UCHL1 facilitates aggregates clearance and enhances neural stem cell activation in spinal cord injury

“…Replacement of lost neurons can be achieved through transplantation of embryonic stem cells or iPSCs followed by induced neurogenesis [39][40][41][42] 43 . In vivo reprogramming of glial cells is emerging to be a great approach, but some limitations about precise glial targeting or accurate differentiation into specific neuronal types still remain 44,45 46 . The mechanism underlying the neurogenic role of UCHL1 in NSCs has been shown to be due to its regulatory effects on ubiquitin level as previously described 46,47 .…”

Current Approaches and Molecular Mechanisms for Directly Reprogramming Fibroblasts Into Neurons and Dopamine Neurons

“…These mechanisms are mainly involved in the transcription factors, mRNAs, RNA interfere (RNAi) or miRNAs to regulate the specific genes such as for neuronal development and maturation ( Rivetti Di Val Cervo et al, 2017 ; Wang et al, 2021 ) or to knockdown the specific genes such as the single RNA bing protein (Ptbp1) to directly reprogramming astrocytes to neurons in vivo ( Zhou et al, 2020 ). A recent study has also systemically reviewed the progress and mechanisms of direct reprogramming in vivo ( Qian C. et al, 2020 ).…”