Mechanisms Of Neural Differentiation Research Articles

Genetic and Epigenetic Regulation of Brain Organoids.

Revealing the mechanisms of neural development and the pathogenesis of neural diseases are one of the most challenging missions in life science. Pluripotent stem cells derived brain organoids mimic the development, maturation, signal generation, and function of human brains, providing unique advantage for neurology. Single-cell RNA sequencing (scRNA-Seq) and multielectrode array independently revealed the similarity between brain organoids and immature human brain at early developmental stages, in the context of gene transcription and dynamic network of neuronal signals. Brain organoids provided the unique opportunity to investigate the underlying mechanism of neural differentiation, senescence, and pathogenesis. In this review, we summarized the latest knowledge and technology in the brain organoid field, the current and potential applications in disease models and pre-clinic studies, with emphasizing the importance of transcriptional and epigenetic analysis.

Cannabidiol prevents depressive-like behaviors through the modulation of neural stem cell differentiation.

Chronic stress impairs radial neural stem cell (rNSC) differentiation and adult hippocampal neurogenesis (AHN), whereas promoting AHN can increase stress resilience against depression. Therefore, investigating the mechanism of neural differentiation and AHN is of great importance for developing antidepressant drugs. The nonpsychoactive phytocannabinoid cannabidiol (CBD) has been shown to be effective against depression. However, whether CBD can modulate rNSC differentiation and hippocampal neurogenesis is unknown. Here, by using the chronic restraint stress (CRS) mouse model, we showed that hippocampal rNSCs mostly differentiated into astrocytes under stress conditions. Moreover, transcriptome analysis revealed that the FoxO signaling pathway was involved in the regulation of this process. The administration of CBD rescued depressive-like symptoms in CRS mice and prevented rNSCs overactivation and differentiation into astrocyte, which was partly mediated by the modulation of the FoxO signaling pathway. These results revealed a previously unknown neural mechanism for neural differentiation and AHN in depression and provided mechanistic insights into the antidepressive effects of CBD.

Therapeutic potential and pharmacological activities of β-eudesmol.

Herbal medicines are attracting the attention of researchers worldwide. β-Eudesmol is one of the most studied and major bioactive sesquiterpenes, mainly extracted from Atractylodes lancea (Thunb) DC. rhizomes. It has potential anti-tumor and anti-angiogenic activities and is an inhibitor of tumor growth by inhibiting angiogenesis by suppressing CREB activation of the growth factor signaling pathway. It also stimulates neurite outgrowth in rat pheochromocytoma cells with activation of mitogen-activated protein kinases. It may be a promising lead compound for enhancing neural function, and it may help to explain the underlying mechanisms of neural differentiation. In this review, we summarized the currently available clinical and preclinical studies describing the therapeutic applications of β-eudesmol.

Prmt4-mediated methylation of NF-κB is critical for neural differentiation of embryonic stem cells

Neural differentiation is a complex process regulated by multiple signaling at different regulatory levels. Though great progresses have been made in understanding the mechanisms of neural differentiation, post-translational regulation of neural differentiation remains largely unknown. In this study, we found Prmt4, one of the methyltransferases catalyzing protein arginine methylation, is highly expressed in neural stem cells (NSCs) and associated with neural differentiation. Knockout of Prmt4 in mESCs blocked neural differentiation by inhibiting NF-κB activation. Mechanistically, Prmt4 interacts with NF-κB component p65 to promote its methylation, resulting in increased activation of NF-κB signaling during neural differentiation. Our study not only identified Prmt4 as novel regulator of neural differentiation, but also highlighted the importance of protein arginine methylation in cell fate transition.

Molecular mechanisms involved in gliomagenesis.

The application of molecular parameters in the World Health Organization classification of central nervous system tumors has advanced remarkably in this field. Large-scale genomic DNA analyses, including gene expression profiling, genome-wide association studies, and single-nucleotide polymorphism analysis, have revealed differences between tumors with the same pathological features. Because mutated genes and their signaling pathways can be targets for therapy, categorizing tumors by molecular parameters facilitates the selection of optimal therapeutic methods. Many genes are either oncogenes or tumor suppressor genes, and many of them are also involved in normal development, such as neural stem cell maintenance and neural differentiation. Moreover, genetic engineering has enabled the generation of tumors that phenocopy human tumors in mice. Here, I will discuss key molecular parameters, mechanisms of neural differentiation, isocitrate dehydrogenases, 1p36/19q13, and p53 in gliomagenesis. Because future therapeutic methods will be determined by the molecular mechanisms of tumors, identification of new parameters is still needed for further classification of glioma.

Efficiency and mechanism of neural differentiation of reprogrammed adipose-derived stem cells in vitro

Objective To investigate the efficiency and mechanism of differentiation of reprogrammed adipose-derived stem cells (ADSCs) to neurons in vitro.Methods ADSCs from rats were cultured in vitro and then purified and identified.ADSCs at the third passage were divided into three groups:ADSCs without lentivirus-mediated gene transfection (blank group),ADSCs transfected with lentivirus carrying no neurogenin2 (Ngn2) (empty virus group) and ADSCs with lentivirus-mediated transfection of Ngn2 (Ngn2 group).All groups were induced in the medium containing cell growth factor for 15 days.The positive expression of neuron-specific nuclear protein (NeuN) in three groups was detected using immunofluorescence method so as to observe the efficiency of neuron differentiation.Expression variances of Mash1,Hes1 and Dll1 in each group were detected by Western blot analysis and the mechanism of differentiation was also discussed.Results After 15 days of induction,positive expression rate of NeuN in Ngn2 group,empty virus group,blank group was 90.12％,45.34％ and 40.26％ respectively,with significant differences among groups (P ＜ 0.01).Western blot analysis showed that Ngn2 group had a significantly higher expression of Dll1 (P ＜0.01) and obvious lower expressions of Hes1 and Mash1 (P ＜0.01),as compared with empty virus group and blank group.However,there were no significant differences of expression levels of Dll1,Mash1 and Hes1 between empty virus group and blank group (P ＞ 0.05).Conclusions After induction,the ratio of neuron differentiation of reprogrammed ADSCs is increased by almost 99％,as compared with simple ADSCs.The increased dfferentiation of reprogrammedADSCs to neurons may be associated with the inhibition of notch signaling through up-regulating Dll1 and down-regulating Mash1 and Hesl. Key words: Adipose tissue ; Stem cells ; Neurons ; Reprogrammed

Epigenetic conversion of human adult bone mesodermal stromal cells into neuroectodermal cell types for replacement therapy of neurodegenerative disorders

Tissue-specific stem cells, such as bone marrow-derived mesodermal stromal cells (MSCs), are thought to be lineage restricted and, therefore, could only be differentiated into cell types of the tissue of origin. Several recent studies, however, suggest that these types of stem cells might be able to break barriers of germ layer commitment and differentiate in vitro and/or in vivo into cells of different tissues, such as neuroectodermal cell types. Recently, protocols for high-yield generation of undifferentiated neural stem cell (NSC)-like cells from MSCs of primate and human origin were reported. Undifferentiated NSCs are commonly used and are more suitable for neurotransplantation compared with fully differentiated neural cells, as differentiated neural cells are well known to poorly survive detachment and subsequent transplantation procedures. These human MSC-derived NSC-like cells (MSC-NSCs) grow in neurosphere-like structures and express high levels of early neuroectodermal markers, but lose characteristics of MSCs. In the presence of selected growth factors, human MSC-NSCs can be differentiated into the three main neural phenotypes: astroglia, oligodendroglia and neurons. Compared with direct differentiation of human MSCs into mature neural cells, the conversion step seems to be essential to generate mature functional neuroectodermal cells. This review describes the techniques for the conversion of human MSCs into NSCs and summarises the data on epigenetic conversion of human MSCs into immature neuroectodermal cells. These cells provide a powerful tool for investigating the molecular mechanisms of neural differentiation, and might serve as an autologous cell source to treat acute and chronic neurodegenerative diseases.

Generation of monoclonal antibodies specific for developmentally regulated antigens of the chicken retina

In order to raise monoclonal antibodies specific for neural antigens that might be involved in regulatory events during histogenesis of the chick visual system, 5 different immunogen fractions were employed in conjunction with 4 immunization regimes. By screening 17,000 hybridoma supernatants from 58 fusion experiments, empirical guidelines were formulated for generation of antibodies with distinct specificities. A number of positive and negative results would not have been predicted from theoretical considerations and emphasize the relevance of empirical data. To substantiate our observations we present 10 monoclonal antibodies that bind to distinct cell types or layers of the retina. Single cell as well as explant cultures in conjunction with Western blot analysis were employed to determine subcellular localization and cell type specificity of selected antibodies. Six antibodies bind specifically to the inner limiting membrane or the optic fiber layer or the inner plexiform layer or the outer plexiform layer. Four recognize selectively ganglion cells or Müller glial cells or presumably subpopulations of amacrine cells. These antibodies promise to be helpful tools to evaluate mechanisms of neural differentiation.