Generation of cerebral cortical GABAergic interneurons from pluripotent stem cells

Abstract

The cerebral cortex functions by the complex interactions of intrinsic and extrinsic neuronal activities, glial actions, and the effects of humoral factors. The intrinsic neuronal influences are mediated by two major subclasses: excitatory glutamatergic neurons that generally have axonal projections extending beyond the neuron's locality and inhibitory GABAergic neurons that generally project locally. These interneurons can be grouped based on morphological, neurochemical, electrophysiological, axonal targeting, and circuit influence characteristics. Cortical interneurons (CIns) can also be grouped based on their origins within the subcortical telencephalon. Interneuron subtypes, of which a dozen or more are thought to exist, are characterized by combinations of these subgrouping features. Due to their well‐documented relevance to the causes of and treatments for neuropsychiatric disorders, and to their remarkable capacity to migrate extensively following transplantation, there has been tremendous interest in generating cortical GABAergic interneurons from human pluripotent stem cells. In this concise review, we discuss recent progress in understanding how interneuron subtypes are generated in vivo, and how that progress is being applied to the generation of rodent and human CIns in vitro. In addition, we will discuss approaches for the rigorous designation of interneuron subgroups or subtypes in transplantation studies, and challenges to this field, including the protracted maturation of human interneurons.

Biomaterial Cues Regulated Differentiation of Neural Stem Cells into GABAergic Neurons through Ca2+/c-Jun/TLX3 Signaling Promoted by Hydroxyapatite Nanorods

“…γ-Aminobutyric acid (GABA) is a major neurotransmitter, which dominates inhibitory conduction . The malfunction of GABAergic neurons is often associated with neurodevelopmental and neurodegenerative disorders, such as epilepsy, Huntington’s disease, Alzheimer’s disease, etc. − There have been attempts to regenerate GABAergic neurons through stem cells based methods, enabling the study of pathogenesis and therapeutics. , In particular, many studies program embryonic stem cells (ESCs) or induce pluripotent stem cells (iPSCs) to derive GABAergic neurons by genetic engineering technology. In comparison, neural stem cells (NSCs) may be better because they are distributed in the central nervous system and capable to terminally differentiate into neurons and glial cells .…”

“…2−4 There have been attempts to regenerate GABAergic neurons through stem cells based methods, enabling the study of pathogenesis and therapeutics. 5,6 In particular, many studies program embryonic stem cells (ESCs) or induce pluripotent stem cells (iPSCs) to derive GABAergic neurons by genetic engineering technology. In comparison, neural stem cells (NSCs) may be better because they are distributed in the central nervous system and capable to terminally differentiate into neurons and glial cells.…”

Coordinated control of neuronal differentiation and wiring by sustained transcription factors

“…This could have large implications for the emerging field of cell replacement therapy. The usage of lineage-specific TFs for the generation of specific neuronal types in vitro have significantly improved the efficiency of these protocols ( 49 ). Some of these TFs, such as Pet1 and Lmx1b for serotonergic neurons ( 50 ) or Lmx1a and Nurr1 for dopaminergic neurons ( 51 ), are also likely to be terminal selectors.…”

Coordinated control of neuronal differentiation and wiring by a sustained code of transcription factors

“…This could have large implications for the emerging field of cell replacement therapy. The current protocols to generate specific neuronal types in vitro mostly rely on recapitulating the signaling conditions that the relevant progenitors normally go through and/or providing lineage-specific TFs to pluripotent stem cells 72, 73 . These require extensive prior knowledge about their development that is only available for a few cell types.…”