Myt1l induced direct reprogramming of pericytes into cholinergic neurons

Liang, Xing; Tan, Chung-I; Wang, Cheng-Kun; Tao, Rongrong; Huang, Yu Jie; Fen, Kui; Fukunaga, Kohji; Huang, Ming; Han, Feng

doi:10.1111/cns.12821

Cited by 29 publications

(24 citation statements)

References 35 publications

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“…Given that astrocyte reactivity is a hallmark of the pathological CNS, RA-derived cholinergic neurons might be potential targets for the treatment of neurodegenerative diseases. Recently, Liang et al reported that MYT1L could directly reprogram human brain vascular pericytes into cholinergic neurons [72], indicating the Myt1l expression in our experiments might be essential for converting and maintaining the cholinergic neuron phenotype. Although these mechanisms remained to be further explored, we believe that the different effects depended on our unique induction cocktail.…”

Section: Discussionmentioning

confidence: 56%

MiR-124 and small molecules synergistically regulate the direct generation of neuronal cells from rat cortical reactive astrocytes

Zheng

Huang

et al. 2020

Preprint

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Background：Irreversible neuron loss caused by central nervous system injuries usually lead to persistent neurological dysfunction. Reactive astrocytes, because of their high proliferative capacity, proximity to neuronal lineage, and significant involvement in glial scarring, are ideal starting cells for neuronal regeneration. Having previously identified several small molecules as important regulators of astrocyte-to-neuron reprogramming, our aim in this study was to explore whether other small molecules and miR-124, a key neural differentiation mediator, could co-regulate reactive astrocyte-to-neuron conversion.Methods: MiR-124, ruxolitinib, SB203580, and forskolin were used to induce postnatal rat cortex reactive astrocytes, and the neuronal phenotype of the induced cells was characterised. To understand the genetic changes, RNA-sequencing analyses were performed on reactive astrocytes, induced neurons, and rat neurons, and the mechanisms underlying the regulatory role of miR-124 during the neuronal conversion was explored.Results：MiR-124, ruxolitinib, SB203580, and forskolin could co-convert rat cortical reactive astrocytes into neurons. The induced cells had reduced astroglial properties, displayed typical neuronal morphologies, and expressed neuronal markers, reflecting 25.9% of cholinergic neurons. Gene analysis revealed that induced neuron gene expression patterns were more similar to that of primary neurons than of initial reactive astrocytes. On the molecular level, miR-124-driven neuronal differentiation of reactive astrocytes was via targeting of the SOX9-NFIA-HES1 axis to inhibit HES1 expression.Conclusions：Providing a novel approach for inducing endogenous rat cortical reactive astrocytes into neurons by co-regulation involving miR-124 and three small molecules, our research has potential implications for inhibiting glial scar formation and promoting neuronal regeneration after central nervous system injury or disease.

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Section: Discussionmentioning

confidence: 56%

MiR-124 and small molecules synergistically regulate the direct generation of neuronal cells from rat cortical reactive astrocytes

Zheng

Huang

et al. 2020

Preprint

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“…We next replaced NEUROG2 with ASCL1, since both of them work as pioneer transcription factors dominantly controlling gene expression and neuronal fates [29,30]. Furthermore, ASCL1 + progenitors can give rise to cholinergic neurons [23,[31][32][33].…”

Section: Rapid and Efficient Generation Of Hibfcns From Adult Human Smentioning

confidence: 99%

Aging-relevant human basal forebrain cholinergic neurons as a cell model for Alzheimer’s disease

Zang

Liu

et al. 2020

Mol Neurodegeneration

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Background Alzheimer’s disease (AD) is an adult-onset mental disorder with aging as a major risk factor. Early and progressive degeneration of basal forebrain cholinergic neurons (BFCNs) contributes substantially to cognitive impairments of AD. An aging-relevant cell model of BFCNs will critically help understand AD and identify potential therapeutics. Recent studies demonstrate that induced neurons directly reprogrammed from adult human skin fibroblasts retain aging-associated features. However, human induced BFCNs (hiBFCNs) have yet to be achieved. Methods We examined a reprogramming procedure for the generation of aging-relevant hiBFCNs through virus-mediated expression of fate-determining transcription factors. Skin fibroblasts were obtained from healthy young persons, healthy adults and sporadic AD patients. Properties of the induced neurons were examined by immunocytochemistry, qRT-PCR, western blotting, and electrophysiology. Results We established a protocol for efficient generation of hiBFCNs from adult human skin fibroblasts. They show electrophysiological properties of mature neurons and express BFCN-specific markers, such as CHAT, p75NTR, ISL1, and VACHT. As a proof-of-concept, our preliminary results further reveal that hiBFCNs from sporadic AD patients exhibit time-dependent TAU hyperphosphorylation in the soma and dysfunctional nucleocytoplasmic transport activities. Conclusions Aging-relevant BFCNs can be directly reprogrammed from human skin fibroblasts of healthy adults and sporadic AD patients. They show promises as an aging-relevant cell model for understanding AD pathology and may be employed for therapeutics identification for AD.

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“…As pericytes have pluripotent individualities, so they have the capacity to trans-differentiate into other cell types such mesenchymal lineage [ 21 , 22 ], neurons, astrocytes, and oligodendrocytes [ 22 , 29 , 104 ]. Type A pericytes, but not types B, participate in scar tissue formation after spinal cord injury.…”

Section: Pericytes Restorative and Stem Cell-like Behavior In Bbb Recmentioning

confidence: 99%

Targeting pericytes for neurovascular regeneration

2019

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Pericytes, as a key cellular part of the blood-brain barrier, play an important role in the maintenance of brain neurovascular unit. These cells participate in brain homeostasis by regulating vascular development and integrity mainly through secreting various factors. Pericytes per se show different restorative properties after blood-brain barrier injury. Upon the occurrence of brain acute and chronic diseases, pericytes provoke immune cells to regulate neuro-inflammatory conditions. Loss of pericytes in distinct neurologic disorders intensifies blood-brain barrier permeability and leads to vascular dementia. The therapeutic potential of pericytes is originated from the unique morphological shape, location, and their ability in providing vast paracrine and juxtacrine interactions. A subset of pericytes possesses multipotentiality and exhibit trans-differentiation capacity in the context of damaged tissue. This review article aimed to highlight the critical role of pericytes in restoration of the blood-brain barrier after injury by focusing on the dynamics of pericytes and cross-talk with other cell types.

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Myt1l induced direct reprogramming of pericytes into cholinergic neurons

Cited by 29 publications

References 35 publications

MiR-124 and small molecules synergistically regulate the direct generation of neuronal cells from rat cortical reactive astrocytes

MiR-124 and small molecules synergistically regulate the direct generation of neuronal cells from rat cortical reactive astrocytes

Aging-relevant human basal forebrain cholinergic neurons as a cell model for Alzheimer’s disease

Targeting pericytes for neurovascular regeneration

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