Regeneration of Functional Neurons After Spinal Cord Injury via in situ NeuroD1-Mediated Astrocyte-to-Neuron Conversion

Puls, Brendan; Ding, Yan; Zhang, Fengyu; Pan, Mengjie; Lei, Zhuofan; Pei, Zifei; Jiang, Mei; Bai, Y.; Forsyth, Cody; Metzger, Morgan; Rana, Tanvi; Zhang, Lei; Ding, Xiaoyun; Keefe, Matthew G.; Cai, Alice; Redilla, Austin; Lai, Michael M.; He, Kevin; Li, Hedong; Chen, Gong

doi:10.3389/fcell.2020.591883

Cited by 79 publications

(75 citation statements)

References 62 publications

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“…investigation. NeuroD1 overexpression has shown promises in regenerative therapy following spinal cord injury and sciatic nerve injuries (Puls et al, 2020;Lai et al, 2020). Given that NeuroD1 partners with other bHLH TFs, discovering such partner TFs may increase success in efforts towards regenerative medicine.…”

Section: Discussionmentioning

confidence: 99%

Tcf12 and NeuroD1 cooperatively drive neuronal migration during cortical development

et al. 2022

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Corticogenesis consists of a series of synchronised events, including fate transition of cortical progenitors, neuronal migration, specification and connectivity. NeuroD1, a basic helix-loop-helix (bHLH) transcription factor (TF), contributes to all of these events, but how it coordinates these independently is still unknown. Here, we demonstrate that NeuroD1 expression is accompanied by a gain of active chromatin at a large number of genomic loci. Interestingly, transcriptional activation of these loci relied on a high local density of adjacent bHLH TFs motifs, including, predominantly, Tcf12. We found that activity and expression levels of Tcf12 were high in cells with induced levels of NeuroD1 that spanned the transition of cortical progenitors from proliferative to neurogenic divisions. Moreover, Tcf12 forms a complex with NeuroD1 and co-occupies a subset of NeuroD1 target loci. This Tcf12-NeuroD1 cooperativity is essential for gaining active chromatin and targeted expression of genes involved in cell migration. By functional manipulation in vivo, we further show that Tcf12 is essential during cortical development for the correct migration of newborn neurons and, hence, for proper cortical lamination.

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Section: Discussionmentioning

confidence: 99%

Tcf12 and NeuroD1 cooperatively drive neuronal migration during cortical development

et al. 2022

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“…Decreased Notch signaling due to stroke was shown to be necessary for astrocyte neurogenesis (Magnusson et al, 2014 ). The transcription factors NeuroD1, SOX2, and ZFP521 can all be used to reprogram astrocytes into neurons or neural stem cells after SCI (Zarei-Kheirabadi et al, 2019a ; Puls et al, 2020 ).…”

Section: Strategies For Astrocyte-targeted Therapymentioning

confidence: 99%

Reactive Astrocytes in Central Nervous System Injury: Subgroup and Potential Therapy

Zhang

Ning

2021

Front. Cell. Neurosci.

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Traumatic central nervous system (CNS) injury, which includes both traumatic brain injury (TBI) and spinal cord injury (SCI), is associated with irreversible loss of neurological function and high medical care costs. Currently, no effective treatment exists to improve the prognosis of patients. Astrocytes comprise the largest population of glial cells in the CNS and, with the advancements in the field of neurology, are increasingly recognized as having key functions in both the brain and the spinal cord. When stimulated by disease or injury, astrocytes become activated and undergo a series of changes, including alterations in gene expression, hypertrophy, the loss of inherent functions, and the acquisition of new ones. Studies have shown that astrocytes are highly heterogeneous with respect to their gene expression profiles, and this heterogeneity accounts for their observed context-dependent phenotypic diversity. In the inured CNS, activated astrocytes play a dual role both as regulators of neuroinflammation and in scar formation. Identifying the subpopulations of reactive astrocytes that exert beneficial or harmful effects will aid in deciphering the pathological mechanisms underlying CNS injuries and ultimately provide a theoretical basis for the development of effective strategies for the treatment of associated conditions. Following CNS injury, as the disease progresses, astrocyte phenotypes undergo continuous changes. Although current research methods do not allow a comprehensive and accurate classification of astrocyte subpopulations in complex pathological contexts, they can nonetheless aid in understanding the roles of astrocytes in disease. In this review, after a brief introduction to the pathology of CNS injury, we summarize current knowledge regarding astrocyte activation following CNS injury, including: (a) the regulatory factors involved in this process; (b) the functions of different astrocyte subgroups based on the existing classification of astrocytes; and (c) attempts at astrocyte-targeted therapy.

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“…A complementary intriguing option that is recently coming to the spotlight is to restore lost functions by exploiting the potential of the astrocytes to trans-differentiate into neurons. In particular, it has been shown that forced expression of selected transcription factors can transform astrocytes into glutamatergic [240][241][242][243][244], GABAergic [243,245,246], dopaminergic [247], retinal [248,249], and motor neurons [250] in mice. Intriguingly, astrocyte trans-differentiation into neurons can be achieved also by downregulating the expression of the polypyrimidine tract binding protein 1 gene (Ptbp1) by either a short hairpin RNA [251] or by expression of an ortholog of CRISPR-Cas13d (CasRx) and two suitable guide RNAs [252].…”

Section: Astrocyte Role In Adult Neurogenesis and As Neuronal Precursorsmentioning

confidence: 99%

Challenges and Opportunities of Targeting Astrocytes to Halt Neurodegenerative Disorders

Valori

Possenti

Brambilla

et al. 2021

Cells

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Neurodegenerative diseases are a heterogeneous group of disorders whose incidence is likely to duplicate in the next 30 years along with the progressive aging of the western population. Non-cell-specific therapeutics or therapeutics designed to tackle aberrant pathways within neurons failed to slow down or halt neurodegeneration. Yet, in the last few years, our knowledge of the importance of glial cells to maintain the central nervous system homeostasis in health conditions has increased exponentially, along with our awareness of their fundamental and multifaced role in pathological conditions. Among glial cells, astrocytes emerge as promising therapeutic targets in various neurodegenerative disorders. In this review, we present the latest evidence showing the astonishing level of specialization that astrocytes display to fulfill the demands of their neuronal partners as well as their plasticity upon injury. Then, we discuss the controversies that fuel the current debate on these cells. We tackle evidence of a potential beneficial effect of cell therapy, achieved by transplanting astrocytes or their precursors. Afterwards, we introduce the different strategies proposed to modulate astrocyte functions in neurodegeneration, ranging from lifestyle changes to environmental cues. Finally, we discuss the challenges and the recent advancements to develop astrocyte-specific delivery systems.

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Regeneration of Functional Neurons After Spinal Cord Injury via in situ NeuroD1-Mediated Astrocyte-to-Neuron Conversion

Cited by 79 publications

References 62 publications

Tcf12 and NeuroD1 cooperatively drive neuronal migration during cortical development

Tcf12 and NeuroD1 cooperatively drive neuronal migration during cortical development

Reactive Astrocytes in Central Nervous System Injury: Subgroup and Potential Therapy

Challenges and Opportunities of Targeting Astrocytes to Halt Neurodegenerative Disorders

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