In Vivo Reprogramming of Striatal NG2 Glia into Functional Neurons that Integrate into Local Host Circuitry

Torper, Olof; Ottosson, Daniella Rylander; Pereira, Maria; Lau, Shong; Cardoso, Tiago; Grealish, Shane; Parmar, Malin

doi:10.1016/j.celrep.2015.06.040

Cited by 177 publications

(166 citation statements)

References 27 publications

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“…Astrocytes and NG2 cells can be reprogrammed to neurons by expressing proneural transcription factors in the cerebral cortical and subcortical regions 17–20 . Recordings from cortical slices and rabies-virus-based tracings indicate that these neurons are functional.…”

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confidence: 99%

Stimulation of functional neuronal regeneration from Müller glia in adult mice

Jorstad

Wilken

Grimes

et al. 2017

Nature

418

481

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Many retinal diseases lead to the loss of retinal neurons and cause visual impairment. The adult mammalian retina has little capacity for regeneration. By contrast, teleost fish functionally regenerate their retina following injury, and Müller glia (MG) are the source of regenerated neurons1–6. The proneural transcription factor Ascl1 is upregulated in MG after retinal damage1,7 in zebrafish and is necessary for regeneration8. Although Ascl1 is not expressed in mammalian MG after injury9, forced expression of Ascl1 in mouse MG induces a neurogenic state in vitro10 and in vivo after NMDA (N-methyl-D-aspartate) damage in young mice11. However, by postnatal day 16, mouse MG lose neurogenic capacity, despite Ascl1 overexpression11. Loss of neurogenic capacity in mature MG is accompanied by reduced chromatin accessibility, suggesting that epigenetic factors limit regeneration. Here we show that MG-specific overexpression of Ascl1, together with a histone deacetylase inhibitor, enables adult mice to generate neurons from MG after retinal injury. The MG-derived neurons express markers of inner retinal neurons, synapse with host retinal neurons, and respond to light. Using an assay for transposase-accessible chromatin with high-throughput sequencing (ATAC–seq), we show that the histone deacetylase inhibitor promotes accessibility at key gene loci in the MG, and allows more effective reprogramming. Our results thus provide a new approach for the treatment of blinding retinal diseases.

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mentioning

confidence: 99%

Stimulation of functional neuronal regeneration from Müller glia in adult mice

Jorstad

Wilken

Grimes

et al. 2017

Nature

418

481

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“…To this end, Parmar and colleagues have developed refined tools to study the conversion of Ng2 glia to GABAergic and glutamatergic neurons and their integration into the host brain (Torper et al, 2015). Using Cre-recombinase-dependent AAV vectors, they delivered Ascl1, Lmx1a, and Nurr1 specifically to NG2 glia in the striatum of adult mice and monitored neuronal conversion and circuit integration through a novel neuron-specific reporter.…”

Section: Introductionmentioning

confidence: 99%

In Vivo Cellular Reprogramming: The Next Generation

Srivastava

DeWitt

2016

Cell

241

187

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SUMMARY Cellular reprogramming technology has created new opportunities in understanding human disease, drug discovery, and regenerative medicine. While a combinatorial code was initially found to reprogram somatic cells to pluripotency, a “second generation” of cellular reprogramming involves lineage-restricted transcription factors and microRNAs that directly reprogram one somatic cell to another. This technology was enabled by gene networks active during development, which induce global shifts in the epigenetic landscape driving cell fate decisions. A major utility of direct reprogramming is the potential of harnessing resident support cells within damaged organs to regenerate lost tissue by converting them into the desired cell type in situ. Here, we review the progress in direct cellular reprogramming with a focus on the paradigm of in vivo reprogramming for regenerative medicine, while pointing to hurdles that must be overcome to translate this technology into future therapeutics.

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“…Delivery of betacellulin (BTC), a member of EGF family, into the lateral ventricle induced the expansion of NSCs and neuroblasts, as well as neurogenesis in the olfactory and dentate gyrus [104]. Interestingly, recent studies have shown that endogenous repair mechanisms are not limited to neurogenic niches as glial cells including astrocytes, oligodendrocyte precursors, and pericytes can be reactivated following ischemia and differentiate into neurons [105][106][107].…”

Section: Exploiting Endogenous Neurogenesismentioning

confidence: 99%

Biomaterial applications in neural therapy and repair

Ghuman

Modo

2016

Chin Neurosurg Jl

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The use of biomaterials, such as hydrogels, as a scaffold to deliver cells and drugs is becoming increasingly common to treat neurological conditions, including stroke. With a limited intrinsic ability to regenerate after injury, innovative tissue engineering strategies have shown the potential of biomaterials in facilitating neural tissue regeneration and functional recovery. Using biomaterials can not only promote the survival and integration of transplanted cells in the existing circuitry, but also support controlled site specific delivery of therapeutic drugs. This review aims to provide the reader an understanding of the brain tissue microenvironment after injury, biomaterial criteria that support tissue repair, commonly used natural and synthetic biomaterials, benefits of incorporating cells and neurotrophic factors, as well as the potential of endogenous neurogenesis in repairing the injured brain.

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In Vivo Reprogramming of Striatal NG2 Glia into Functional Neurons that Integrate into Local Host Circuitry

Cited by 177 publications

References 27 publications

Stimulation of functional neuronal regeneration from Müller glia in adult mice

Stimulation of functional neuronal regeneration from Müller glia in adult mice

In Vivo Cellular Reprogramming: The Next Generation

Biomaterial applications in neural therapy and repair

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