Non-engineered and Engineered Adult Neurogenesis in Mammalian Brains

Lei, Wenliang; Li, Wen; Ge, Longjiao; Chen, Gong

doi:10.3389/fnins.2019.00131

Cited by 23 publications

(16 citation statements)

References 157 publications

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“…It shows that some permissive signals are lacking in the brain environment [like SHH signaling, (Sirko et al, )] or conversely, that restrictive factors prevent astrocytes from returning to a multipotent state and differentiating into neurons [like Notch signaling, (Magnusson et al, )]. Significant efforts are made to identify and target such factors, to promote the neurogenic potential of reactive astrocytes and their reconstruction of damaged neuronal circuits [for a complete review, see (Lei, Li, Ge, & Chen, )].…”

Section: Where Do Reactive Astrocytes Come From or What Do They Become?mentioning

confidence: 99%

Questions and (some) answers on reactive astrocytes

Escartin

Guillemaud

Sauvage

2019

Glia

207

180

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Astrocytes are key cellular partners for neurons in the central nervous system. Astrocytes react to virtually all types of pathological alterations in brain homeostasis by significant morphological and molecular changes. This response was classically viewed as stereotypical and is called astrogliosis or astrocyte reactivity. It was long considered as a nonspecific, secondary reaction to pathological conditions, offering no clues on disease‐causing mechanisms and with little therapeutic value. However, many studies over the last 30 years have underlined the crucial and active roles played by astrocytes in physiology, ranging from metabolic support, synapse maturation, and pruning to fine regulation of synaptic transmission. This prompted researchers to explore how these new astrocyte functions were changed in disease, and they reported alterations in many of them (sometimes beneficial, mostly deleterious). More recently, cell‐specific transcriptomics revealed that astrocytes undergo massive changes in gene expression when they become reactive. This observation further stressed that reactive astrocytes may be very different from normal, nonreactive astrocytes and could influence disease outcomes. To make the picture even more complex, both normal and reactive astrocytes were shown to be molecularly and functionally heterogeneous. Very little is known about the specific roles that each subtype of reactive astrocytes may play in different disease contexts. In this review, we have interrogated researchers in the field to identify and discuss points of consensus and controversies about reactive astrocytes, starting with their very name. We then present the emerging knowledge on these cells and future challenges in this field.

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Section: Where Do Reactive Astrocytes Come From or What Do They Become?mentioning

confidence: 99%

Questions and (some) answers on reactive astrocytes

Escartin

Guillemaud

Sauvage

2019

Glia

207

180

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“…Differences range from structural to functional. For the scope of this review, it is useful to list only a few, comprising: the different dynamic of neuronal maturation, with much longer times in non-human primates than in rodents, and lack of human data; the different cytoarchitecture of the SVZ in rodents compared to primates; the migration of newborn cells from the SVZ to the olfactory bulb in rodents and monkeys, with sparse evidence for humans; very pronounced striatal adult neurogenesis in humans compared to rodents and non-human primates (reviewed in [42]); finally, a different number of neurogenic zones detectable in adult rodents, monkeys and humans [43] (Figure 2).…”

Section: Radiation Effects On Cognitive Functionmentioning

confidence: 99%

Neurocognitive Decline Following Radiotherapy: Mechanisms and Therapeutic Implications

Pazzaglia

Briganti

Mancuso

et al. 2020

Cancers

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The brain undergoes ionizing radiation (IR) exposure in many clinical situations, particularly during radiotherapy for malignant brain tumors. Cranial radiation therapy is related with the hazard of long-term neurocognitive decline. The detrimental ionizing radiation effects on the brain closely correlate with age at treatment, and younger age associates with harsher deficiencies. Radiation has been shown to induce damage in several cell populations of the mouse brain. Indeed, brain exposure causes a dysfunction of the neurogenic niche due to alterations in the neuronal and supporting cell progenitor signaling environment, particularly in the hippocampus—a region of the brain critical to memory and cognition. Consequent deficiencies in rates of generation of new neurons, neural differentiation and apoptotic cell death, lead to neuronal deterioration and lasting repercussions on neurocognitive functions. Besides neural stem cells, mature neural cells and glial cells are recognized IR targets. We will review the current knowledge about radiation-induced damage in stem cells of the brain and discuss potential treatment interventions and therapy methods to prevent and mitigate radiation related cognitive decline.

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“…In vivo neuronal reprogramming has recently emerged as a novel technology to regenerate functional new neurons from endogenous glial cells by overexpressing neurogenic transcription factors in the CNS (Grande et al, 2013;Niu et al, 2013;Guo et al, 2014;Liu et al, 2015Liu et al, , 2020Gascon et al, 2016;Li and Chen, 2016;Barker et al, 2018;Lei et al, 2019;Chen et al, 2020;Wu et al, 2020). In the injured spinal cord, a combination of growth factor treatment and forced expression of the neurogenic transcription factor Neurogenin 2 (Ngn2) has been reported to stimulate neurogenesis from neural progenitors (Ohori et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

Regeneration of Functional Neurons After Spinal Cord Injury via in situ NeuroD1-Mediated Astrocyte-to-Neuron Conversion

Puls

Ding

Zhang

et al. 2020

Front. Cell Dev. Biol.

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Spinal cord injury (SCI) often leads to impaired motor and sensory functions, partially because the injury-induced neuronal loss cannot be easily replenished through endogenous mechanisms. In vivo neuronal reprogramming has emerged as a novel technology to regenerate neurons from endogenous glial cells by forced expression of neurogenic transcription factors. We have previously demonstrated successful astrocyte-to-neuron conversion in mouse brains with injury or Alzheimer's disease by overexpressing a single neural transcription factor NeuroD1. Here we demonstrate regeneration of spinal cord neurons from reactive astrocytes after SCI through AAV NeuroD1-based gene therapy. We find that NeuroD1 converts reactive astrocytes into neurons in the dorsal horn of stab-injured spinal cord with high efficiency (~95%). Interestingly, NeuroD1-converted neurons in the dorsal horn mostly acquire glutamatergic neuronal subtype, expressing spinal cord-specific markers such as Tlx3 but not brain-specific markers such as Tbr1, suggesting that the astrocytic lineage and local microenvironment affect the cell fate after conversion. Electrophysiological recordings show that the NeuroD1-converted neurons can functionally mature and integrate into local spinal cord circuitry by displaying repetitive action potentials and spontaneous synaptic responses. We further show that NeuroD1-mediated neuronal conversion can occur in the contusive SCI model with a long delay after injury, allowing future studies to further evaluate this in vivo reprogramming technology for functional recovery after SCI. In conclusion, this study may suggest a paradigm shift from classical axonal regeneration to neuronal regeneration for spinal cord repair, using in vivo astrocyte-to-neuron conversion technology to regenerate functional new neurons in the gray matter.

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Non-engineered and Engineered Adult Neurogenesis in Mammalian Brains

Cited by 23 publications

References 157 publications

Questions and (some) answers on reactive astrocytes

Questions and (some) answers on reactive astrocytes

Neurocognitive Decline Following Radiotherapy: Mechanisms and Therapeutic Implications

Regeneration of Functional Neurons After Spinal Cord Injury via in situ NeuroD1-Mediated Astrocyte-to-Neuron Conversion

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