Sleep is evolutionarily conserved across all species, and impaired sleep is a common trait of the diseased brain. Sleep quality decreases as we age, and disruption of the regular sleep architecture ...is a frequent antecedent to the onset of dementia in neurodegenerative diseases. The glymphatic system, which clears the brain of protein waste products, is mostly active during sleep. Yet the glymphatic system degrades with age, suggesting a causal relationship between sleep disturbance and symptomatic progression in the neurodegenerative dementias. The ties that bind sleep, aging, glymphatic clearance, and protein aggregation have shed new light on the pathogenesis of a broad range of neurodegenerative diseases, for which glymphatic failure may constitute a therapeutically targetable final common pathway.
A variety of neurological disorders are attractive targets for stem and progenitor cell-based therapy. Yet many conditions are not, whether by virtue of an inhospitable disease environment, poorly ...understood pathophysiology, or poor alignment of donor cell capabilities with patient needs. Moreover, some disorders may be medically feasible targets but are not practicable, in light of already available treatments, poor risk-benefit and cost-benefit profiles, or resource limitations. This Perspective seeks to define those neurological conditions most appropriate for cell replacement therapy by considering its potential efficacy and clinical feasibility in those disorders, as well as potential impediments to its application.
A variety of neurological disorders are attractive targets for stem and progenitor cell-based therapy, but there are some conditions which are not. This Perspective seeks to define those neurological conditions most appropriate for cell replacement therapy by considering the potential efficacy, clinical feasibility, and impediments to application.
How to make an oligodendrocyte Goldman, Steven A; Kuypers, Nicholas J
Development (Cambridge),
2015-Dec-01, Letnik:
142, Številka:
23
Journal Article
Recenzirano
Odprti dostop
Oligodendrocytes produce myelin, an insulating sheath required for the saltatory conduction of electrical impulses along axons. Oligodendrocyte loss results in demyelination, which leads to impaired ...neurological function in a broad array of diseases ranging from pediatric leukodystrophies and cerebral palsy, to multiple sclerosis and white matter stroke. Accordingly, replacing lost oligodendrocytes, whether by transplanting oligodendrocyte progenitor cells (OPCs) or by mobilizing endogenous progenitors, holds great promise as a therapeutic strategy for the diseases of central white matter. In this Primer, we describe the molecular events regulating oligodendrocyte development and how our understanding of this process has led to the establishment of methods for producing OPCs and oligodendrocytes from embryonic stem cells and induced pluripotent stem cells, as well as directly from somatic cells. In addition, we will discuss the safety of engrafted stem cell-derived OPCs, as well as approaches by which to modulate their differentiation and myelinogenesis in vivo following transplantation.
Human astrocytes are larger and more complex than those of infraprimate mammals, suggesting that their role in neural processing has expanded with evolution. To assess the cell-autonomous and ...species-selective properties of human glia, we engrafted human glial progenitor cells (GPCs) into neonatal immunodeficient mice. Upon maturation, the recipient brains exhibited large numbers and high proportions of both human glial progenitors and astrocytes. The engrafted human glia were gap-junction-coupled to host astroglia, yet retained the size and pleomorphism of hominid astroglia, and propagated Ca2+ signals 3-fold faster than their hosts. Long-term potentiation (LTP) was sharply enhanced in the human glial chimeric mice, as was their learning, as assessed by Barnes maze navigation, object-location memory, and both contextual and tone fear conditioning. Mice allografted with murine GPCs showed no enhancement of either LTP or learning. These findings indicate that human glia differentially enhance both activity-dependent plasticity and learning in mice.
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► Neonatal implantation of human glial progenitors generates glial chimeric brains ► Hominid-specific astrocytic properties are retained in a cell-autonomous fashion ► Human glial chimerization enhances TNFα-dependent long-term potentiation ► Human glial chimeric mice are faster learners across a range of behavioral tests
Human glial progenitors transplanted into the mouse brain integrate to form a chimeric forebrain and improve performance in a broad range of learning tests.
Neonatal engraftment by oligodendrocyte progenitor cells (OPCs) permits the myelination of the congenitally dysmyelinated brain. To establish a potential autologous source of these cells, we ...developed a strategy by which to differentiate human induced pluripotent stem cells (hiPSCs) into OPCs. From three hiPSC lines, as well as from human embryonic stem cells (hESCs), we generated highly enriched OLIG2+/PDGFRα+/NKX2.2+/SOX10+ human OPCs, which could be further purified using fluorescence-activated cell sorting. hiPSC OPCs efficiently differentiated into both myelinogenic oligodendrocytes and astrocytes, in vitro and in vivo. Neonatally engrafted hiPSC OPCs robustly myelinated the brains of myelin-deficient shiverer mice and substantially increased their survival. The speed and efficiency of myelination by hiPSC OPCs was higher than that previously observed using fetal-tissue-derived OPCs, and no tumors from these grafts were noted as long as 9 months after transplant. These results suggest the potential utility of hiPSC-derived OPCs in treating disorders of myelin loss.
► Myelinating oligodendrocyte progenitor cells (OPCs) were generated from human iPSCs ► hiPSC OPCs myelinated the brains of shiverer mice and increased their survival ► Myelination by hiPSC OPCs was faster than that of fetal-tissue-derived OPCs ► hiPSC OPCs produced both astrocytes and oligodendrocytes and were not tumorigenic
Oligodendrocyte progenitor cells derived from human iPSCs can improve function and survival in mice with a myelination defect, suggesting that autologously derived cells could be used to treat human myelination diseases.
The current widespread outbreak of Zika virus (ZIKV) infection has been linked to severe clinical birth defects, particularly microcephaly, warranting urgent study of the molecular mechanisms ...underlying ZIKV pathogenesis. Akt-mTOR signaling is one of the key cellular pathways essential for brain development and autophagy regulation. Here, we show that ZIKV infection of human fetal neural stem cells (fNSCs) causes inhibition of the Akt-mTOR pathway, leading to defective neurogenesis and aberrant activation of autophagy. By screening the three structural proteins and seven nonstructural proteins present in ZIKV, we found that two, NS4A and NS4B, cooperatively suppress the Akt-mTOR pathway and lead to cellular dysregulation. Corresponding proteins from the closely related dengue virus do not have the same effect on neurogenesis. Thus, our study highlights ZIKV NS4A and NS4B as candidate determinants of viral pathogenesis and identifies a mechanism of action for their effects, suggesting potential targets for anti-ZIKV therapeutic intervention.
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•ZIKV infects human fNSCs, leading to defective neurogenesis and increased autophagy•Expression of ZIKV NS4A and NS4B blocks neurogenesis and promotes autophagy•Two ZIKV proteins, NS4A and NS4B, inhibit Akt-mTOR signaling
Liang et al. show that after infection of human fetal neural stem cells, the ZIKV proteins NS4A and NS4B inhibit the Akt-mTOR signaling pathway, disrupting neurogenesis and inducing autophagy. Their study therefore identifies candidate molecular determinants of ZIKV pathogenesis and highlights potential targets for therapeutic intervention.
The lymphatic system performs essential physiological functions for protein homeostasis and immune surveillance; hence, the apparent absence of conventional lymphatic vessels from the CNS has ...remained a persistent mystery of neuroscience, particularly in light of the exquisite sensitivity of neurons to the composition of their extracellular environment. Genetic ablation of the dural lymphatic vasculature in mice slowed the clearance of tracers injected into the brain interstitium and prevented them from reaching the deep cervical lymph nodes, showing that the clearance of solutes from the brain interstitium was dependent upon their movement along these sinus-associated lymphatic vessels.6 One caveat shared by both studies is their implication that cervical nodes provide an intermediate way-station for fluid travelling from the brain interstitial space to the systemic circulation.
Microglia are integral functional elements of the central nervous system, but the contribution of these cells to the structural integrity of the neurovascular unit has not hitherto been assessed. We ...show here that following blood–brain barrier (BBB) breakdown, P2RY12 (purinergic receptor P2Y, G-protein coupled, 12)-mediated chemotaxis of microglia processes is required for the rapid closure of the BBB. Mice treated with the P2RY12 inhibitor clopidogrel, as well as those in which P2RY12 was genetically ablated, exhibited significantly diminished movement of juxtavascularmicroglial processes and failed to close laser-induced openings of the BBB. Thus, microglial cells play a previously unrecognized protective role in the maintenance of BBB integrity following cerebrovascular damage. Because clopidogrel antagonizes the platelet P2Y12 receptor, it is widely prescribed for patients with coronary artery and cerebrovascular disease. As such, these observations suggest the need for caution in the postincident continuation of P2RY12-targeted platelet inhibition.
Malignant gliomas are aggressive brain tumors with limited therapeutic options, and improvements in treatment require a deeper molecular understanding of this disease. As in other cancers, recent ...studies have identified highly tumorigenic subpopulations within malignant gliomas, known generally as cancer stem cells. Here, we demonstrate that glioma stem cells (GSCs) produce nitric oxide via elevated nitric oxide synthase-2 (NOS2) expression. GSCs depend on NOS2 activity for growth and tumorigenicity, distinguishing them from non-GSCs and normal neural progenitors. Gene expression profiling identified many
NOS2-regulated genes, including the cell-cycle inhibitor cell division autoantigen-1 (
CDA1). Further, high
NOS2 expression correlates with decreased survival in human glioma patients, and NOS2 inhibition slows glioma growth in a murine intracranial model. These data provide insight into how GSCs are mechanistically distinct from their less tumorigenic counterparts and suggest that NOS2 inhibition may be an efficacious approach to treating this devastating disease.
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► Glioma stem cell proliferation is supported by nitric oxide synthase-2 (NOS2) ► Nonstem glioma cells and normal neural stem cells are not dependent on NOS2 ► NOS2 affects glioma stem cell gene expression, including cell-cycle inhibitor CDA1 ► Pharmacological inhibition of NOS2 attenuates glioma growth in vivo
Astroglial complexity and pleomorphism have increased significantly with hominid evolution. This suggests a potential association between glial evolution and the development of human cognition, as ...well as between glial evolution and the advent of human‐selective neurodegenerative and neuropsychiatric disorders.
The data discussed herein, including studies in human glial chimeric mice in which mouse glial cells are replaced, in part, by human glia, suggest that the development of species‐specific human cognitive capabilities and psychopathologies alike each reflect the effects of astrocytic and oligodendrocytic evolution on both the functional competence and complexity of the adult human brain.
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