Браузер не даёт сохранять данные (например, приватный режим): закладки пропадут после закрытия вкладки.
Поиск статей PubMed
Ключевые слова, автор, журнал, годы — результаты из PubMed, аннотации с переводом на русский, закладки в браузере.
Найдено: 5 460
Страница 124 из 546-
Human 3D cellular model of hypoxic brain injury of prematurity.
Owing to recent medical and technological advances in neonatal care, infants born extremely premature have increased survival rates1,2. After birth, these infants are at high risk of hypoxic episodes because of lung immaturity, hypotension and lack of cerebral-flow regulation, and can develop a severe condition called encephalopathy of prematurity3. Over 80% of infants born before post-conception week 25 have moderate-to-severe long-term neurodevelopmental impairments4. The susceptible cell types in the cerebral cortex and the molecular mechanisms underlying associated gray-matter defects in premature infants remain unknown. Here we used human three-dimensional brain-region-specific organoids to study the effect of oxygen deprivation on corticogenesis. We identified specific defects in intermediate progenitors, a cortical cell type associated with the expansion of the human cerebral cortex, and showed that these are related to the unfolded protein response and changes. Moreover, we verified these findings in human primary cortical tissue and demonstrated that a small-molecule modulator of the unfolded protein response pathway can prevent the reduction in intermediate progenitors following hypoxia. We anticipate that this human cellular platform will be valuable for studying the environmental and genetic factors underlying injury in the developing human brain.
-
MECP2T203M mutation disrupts neurogenesis in human cerebral organoids by altering chromatin dynamics and transcriptional regulation.
Rett syndrome (RTT) is a severe, neurodevelopmental disorder caused primarily by loss-of-function mutations in the methyl-CpG-binding protein 2 (MECP2) gene. Although the regulatory role of MECP2 in neuronal development and postnatal functions has been thoroughly investigated, its mechanisms in prenatal human brain development remain elusive. Here, we successfully established a stable culture of cerebral organoids derived from human induced pluripotent stem cells (hiPSCs) to mimic the MECP2 mutant in the prenatal brain that causes RTT. We found that T203M, a human-specific MECP2 point mutation, disrupts neurogenesis. To systematically infer the molecular mechanisms underlying aberrant neurogenesis, we applied an integrative multi-omics approach to comprehensively characterize the associated chromatin dynamics and transcriptomic alterations. Our findings revealed a notably open chromatin state in the organoids with a mutated MECP2, particularly in the enhancer regions with a high proportion of adenine (A) and thymine (T) bases. This alteration induced the expression of genes related to proliferation but suppressed those associated with neuronal differentiation. Furthermore, through multi-omics, we uncovered a MECP2-mutation-driven, cell-type-specific, and disease-related multi-layered regulatory network contributing to development states with high pluripotency but low differentiation, and abnormal neurogenesis. Our study provides a comprehensive resource to elucidate the molecular mechanisms underlying the pathological processes of RTT during prenatal brain development.
-
Polypeptide composition of membranes derived from neuronal and glial cells.
-
Human-specific ARHGAP11B ensures human-like basal progenitor levels in hominid cerebral organoids.
The human-specific gene ARHGAP11B has been implicated in human neocortex expansion. However, the extent of ARHGAP11B's contribution to this expansion during hominid evolution is unknown. Here we address this issue by genetic manipulation of ARHGAP11B levels and function in chimpanzee and human cerebral organoids. ARHGAP11B expression in chimpanzee cerebral organoids doubles basal progenitor levels, the class of cortical progenitors with a key role in neocortex expansion. Conversely, interference with ARHGAP11B's function in human cerebral organoids decreases basal progenitors down to the chimpanzee level. Moreover, ARHGAP11A or ARHGAP11B rescue experiments in ARHGAP11A plus ARHGAP11B double-knockout human forebrain organoids indicate that lack of ARHGAP11B, but not of ARHGAP11A, decreases the abundance of basal radial glia-the basal progenitor type thought to be of particular relevance for neocortex expansion. Taken together, our findings demonstrate that ARHGAP11B is necessary and sufficient to ensure the elevated basal progenitor levels that characterize the fetal human neocortex, suggesting that this human-specific gene was a major contributor to neocortex expansion during human evolution.
-
Electron optic study of the lesions induced by Creutzfeldt--Jakob disease virus in the guinea pig.
An electron microscopic study was performed in brain sections from guinea pigs with experimental Creutzfeldt-Jakob disease. Vacuolation of the neuropil, dilatations of the endoplasmic reticulum and lipid accumulations were observed in the grey matter, while the white matter exhibited intramyelinic vacuoles.
-
Vascularizing the brain organoids.
-
The fine structure of nuclear inclusions in the brain of experimental golden hamsters.
-
Cerebral organoids derived from Sandhoff disease-induced pluripotent stem cells exhibit impaired neurodifferentiation.
Sandhoff disease, one of the GM2 gangliosidoses, is a lysosomal storage disorder characterized by the absence of β-hexosaminidase A and B activity and the concomitant lysosomal accumulation of its substrate, GM2 ganglioside. It features catastrophic neurodegeneration and death in early childhood. How the lysosomal accumulation of ganglioside might affect the early development of the nervous system is not understood. Recently, cerebral organoids derived from induced pluripotent stem (iPS) cells have illuminated early developmental events altered by disease processes. To develop an early neurodevelopmental model of Sandhoff disease, we first generated iPS cells from the fibroblasts of an infantile Sandhoff disease patient, then corrected one of the mutant HEXB alleles in those iPS cells using CRISPR/Cas9 genome-editing technology, thereby creating isogenic controls. Next, we used the parental Sandhoff disease iPS cells and isogenic HEXB-corrected iPS cell clones to generate cerebral organoids that modeled the first trimester of neurodevelopment. The Sandhoff disease organoids, but not the HEXB-corrected organoids, accumulated GM2 ganglioside and exhibited increased size and cellular proliferation compared with the HEXB-corrected organoids. Whole-transcriptome analysis demonstrated that development was impaired in the Sandhoff disease organoids, suggesting that alterations in neuronal differentiation may occur during early development in the GM2 gangliosidoses.
-
Symbolic Value of Brain Organoids: Shifting the Focus from Consciousness to Sociocultural Perspectives on Resemblance.
-
Engineering of human brain organoids with a functional vascular-like system.
Human cortical organoids (hCOs), derived from human embryonic stem cells (hESCs), provide a platform to study human brain development and diseases in complex three-dimensional tissue. However, current hCOs lack microvasculature, resulting in limited oxygen and nutrient delivery to the inner-most parts of hCOs. We engineered hESCs to ectopically express human ETS variant 2 (ETV2). ETV2-expressing cells in hCOs contributed to forming a complex vascular-like network in hCOs. Importantly, the presence of vasculature-like structures resulted in enhanced functional maturation of organoids. We found that vascularized hCOs (vhCOs) acquired several blood-brain barrier characteristics, including an increase in the expression of tight junctions, nutrient transporters and trans-endothelial electrical resistance. Finally, ETV2-induced endothelium supported the formation of perfused blood vessels in vivo. These vhCOs form vasculature-like structures that resemble the vasculature in early prenatal brain, and they present a robust model to study brain disease in vitro.