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Physiological, pathological, and engineered cell identity reprogramming in the central nervous system

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Multipotent neural stem cells persist in restricted regions of the adult mammalian central nervous system. These proliferative cells differentiate into diverse neuron subtypes to maintain neural homeostasis. This endogenous process can be reprogrammed as a compensatory response to physiological cues, traumatic injury, and neurodegeneration. In addition to innate neurogenesis, recent research has demonstrated that new neurons can be engineered via cell identity reprogramming in non‐neurogenic regions of the adult central nervous system. A comprehensive understanding of these reprogramming mechanisms will be essential to the development of therapeutic neural regeneration strategies that aim to improve functional recovery after injury and neurodegeneration. WIREs Dev Biol 2016, 5:499–517. doi: 10.1002/wdev.234 This article is categorized under: Adult Stem Cells, Tissue Renewal, and Regeneration > Stem Cell Differentiation and Reversion Adult Stem Cells, Tissue Renewal, and Regeneration > Regeneration Adult Stem Cells, Tissue Renewal, and Regeneration > Environmental Control of Stem Cells
Neurogenesis in the adult brain. The subgranular zone (SGZ) of the dentate gyrus and subventricular zone (SVZ) of the lateral ventricle (LV) retain the capacity for neurogenesis into adulthood. SGZ neural stem cells (NSCs) (type 1 cells) generate nonradial precursor (type 2) cells, which proliferate and develop into neuroblasts and ultimately differentiated granule neurons within the dentate gyrus. By contrast, active SVZ NSCs (type B cells) first generate fast‐dividing transit amplifying progenitor (type C) cells, convert into neuroblasts, and migrate through the rostral migratory stream (RMS) into the olfactory bulb (OB) for differentiation into GABA‐positive olfactory neurons. EP, ependymal cells; GCL, granule cell layer; ML, molecular layer.
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Clinical barriers to engineered reprogramming. Numerous safety‐ and efficacy‐related hurdles have hindered the clinical application of neural reprogramming technologies. Viral‐based gene delivery, limited success of in vivo genetic correction technologies, iPSC tumorigenicity, and high‐efficiency production of functional neurons with homogenous identity have limited the utility of reprogramming technologies in the clinic. Solutions to these issues such as small molecule‐based reprogramming and in vivo transdifferentiation are currently under development.
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Engineered cell identity reprogramming. Cell identity can be engineered using pluripotency‐based, progenitor‐based or transdifferentiation strategies. Pluripotency‐based reprogramming strategies involve the dedifferentiation of a somatic cell and respecification of the desired cell type from the resultant iPSC. Progenitor‐based reprogramming converts a somatic cell into an expandable neural progenitor that further differentiates into the desired neural lineage. Transdifferentiation enables the direct generation of functional neurons from differentiated non‐neuronal cell types.
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Historical timeline of pluripotency research. This timeline highlights 11 milestone events that defined our understanding of developmental and engineered pluripotency.
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Neural reprogramming in the adult spinal cord. Multiple cell types in the adult spinal cord reprogram in response to injury or engineered stimuli. In response to traumatic injury or neuroinflammation, resident spinal cells dedifferentiate, proliferate, and produce multiple glial lineages. However, the existence of endogenous lesion‐induced neurogenesis remains debated. The in vivo generation of mature neurons has been achieved using both neuroblast‐based and direct reprogramming strategies.
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