Abstract
Glial progenitor cells are widely distributed in brain parenchyma and represent a suitable target for future therapeutic interventions that generate new neurons via in situ reprogramming. Previous studies have shown successful reprogramming of mouse glia into neurons whereas the conversion of human glial cells remains challenging due to the limited accessibility of human brain tissue. Here, we have used a recently developed stem cell-based model of human glia progenitor cells (hGPCs) for direct neural reprogramming by overexpressing a set of transcription factors involved in GABAergic interneuron fate specification. GABAergic interneurons play a key role in balancing excitatory and inhibitory neural circuitry in the brain and loss or dysfunction of these have been implicated in several neurological disorders such as epilepsy, schizophrenia, and autism. Our results demonstrate that hGPCs successfully convert into functional induced neurons with postsynaptic activity within a month. The induced neurons have properties of GABAergic neurons, express subtype-specific interneuron markers (e.g. parvalbumin) and exhibit a complex neuronal morphology with extensive dendritic trees. The possibility of inducing GABAergic interneurons from a renewable in vitro hGPC system could provide a foundation for the development of therapies for interneuron pathologies.
Highlights
Direct neuronal reprogramming is a rapidly emerging field of research where non-neuronal cells can be converted into induced neurons using key combinations of transcription factors, microRNA, and/or a cocktail of chemical compounds that manipulate pathways involved in neuronal fate and functions
We assessed the phenotype of the glial population by fluorescent activated cell sorting (FACS), which confirmed the presence of three subtypes of glial progenitors (Table S3): primarily oligodendrocyte-biased
HESC-derived Glial progenitor cells (GPCs) were transduced with Ascl1, Dlx5, Lhx6, Sox2, and Foxg1 where Sox2 and Foxg1 were de-activated via doxycycline withdrawal after protein level using immunocytochemistry
Summary
Direct neuronal reprogramming is a rapidly emerging field of research where non-neuronal cells can be converted into induced neurons (iNs) using key combinations of transcription factors, microRNA, and/or a cocktail of chemical compounds that manipulate pathways involved in neuronal fate and functions. The ability to induce subtype-specific interneurons via in situ direct reprogramming may represent an alternative therapeutic approach to restore the lost neuronal function in the brain. In this regard, the conversion of human cells into clinically relevant interneurons provides an important step toward developing a new cell repair strategy. The induced cultures consisted of a heterogenous population of several interneuron subtypes and a low proportion of non-GABAergic cells This is the first successful conversion of hGPCs into functional and subtype-specific GABAergic neurons that might have potential for cell-restorative therapies, and for disease modeling strategies
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