Differentiation Of Neural Cells Research Articles

Filamin A in focus: unravelling the multifaceted roles of filamin A in neurodevelopment and neurological disorders.

Neurodevelopment is an intricate process encompassing the proliferation, differentiation, migration, and maturation of neural cells. Disruptions in these tightly regulated events can lead to a variety of neurodevelopmental disorders. Filamin A (FLNA), a key actin-binding protein, plays a pivotal role in regulating neuronal migration, morphological development, and synaptic connectivity by modulating actin cytoskeletal dynamics and interacting with various signaling pathways. FLNA mutations are implicated in several neurodevelopmental disorders, such as periventricular nodular heterotopia (PVNH), leading to neurological symptoms such as epilepsy, intellectual disability, and cognitive impairments. In this review, we delve into FLNA's multifaceted role in neurodevelopment, with a particular focus on its contributions to neuronal migration, dendritic and axonal growth, and mechanotransduction. Additionally, we examine how FLNA dysregulation leads to neurodevelopmental abnormalities, providing insights into its potential as a therapeutic target. By elucidating the molecular mechanisms through which FLNA governs neurodevelopment, we aim to advance our understanding of its crucial role in both brain formation and disease pathogenesis.

High-resolution spatial transcriptomics and cell lineage analysis reveal spatiotemporal cell fate determination during craniofacial development

The differentiation of post-migratory cranial neural crest cells (CNCCs) into distinct mesenchymal lineages is crucial for craniofacial development. Here we report a high-resolution spatiotemporal transcriptomic and cell-type atlas of CNCC-derived mesenchymal lineage diversification during mouse palatogenesis. We systematically defined each mesenchymal cell type by mapping their transcriptomic profiles to spatial identities. Integrative analysis of spatial transcriptomic data from E12.5 to E15.5 further revealed mesenchymal lineage establishment at or prior to initiation of palatogenesis. We also identified a heterogeneous Sox9+ mesenchymal progenitor population at the onset of palatal development, with subpopulations already activating early lineage-specific markers. In vivo lineage tracing using these early lineage-specific markers demonstrated that distinct mesenchymal populations are established as early as E10.5 to E11.5, preceding palatal development, and contribute to their respective lineages. Together, our findings reveal the comprehensive, dynamic molecular and cellular landscape of palate development and shed light on cell fate regulation during embryogenesis.

Functional Analysis of Antipsychotics in Human iPSC-Based Neural Progenitor 2D and 3D Schizophrenia Models.

Schizophrenia is a complex psychiatric disorder of complex etiology. Despite decades of antipsychotic drug development and treatment, the mechanisms underlying cellular drug effects remain incompletely understood. Induced pluripotent stem cell (iPSC)-based disease and pharmacological modelling offer new avenues for drug development. In this study, we explored the development of two- and three-dimensional neural progenitor cultures and the impact of different antipsychotics in a schizophrenia model. Four human iPSC lines, including two carrying a de novo ZMYND11 gene mutation associated with schizophrenia, were differentiated into hippocampal neural progenitor cells (NPCs), cultured either in monolayers or as 3D spheroids. While in monolayers the proliferation of the NPCs was similar, spheroids showed significant differences in scattered cell number and outgrowth size between schizophrenia mutant and wild-type NPCs. Since there is only limited information about the effects of antipsychotic agents on neural progenitor cell proliferation and differentiation, we investigated the effects of three molecules, representing three subgroups of antipsychotics, in the 2D and 3D NPC models. Our findings suggest that cell adhesion may play a crucial role in the molecular disease pathways of schizophrenia, highlighting the value of spheroid models for mechanistic and drug development studies. These studies may significantly help our understanding of the effects of schizophrenia on neural development and the response of progenitors to antipsychotic medications.

Hippocampal transcriptome analysis in ClockΔ19 mice identifies pathways associated with glial cell differentiation and myelination.

Hippocampal transcriptome analysis in ClockΔ19 mice identifies pathways associated with glial cell differentiation and myelination.

DOT1L in neural development and neurological and psychotic disorders.

DOT1L in neural development and neurological and psychotic disorders.

Temporally discordant chromatin accessibility and DNA demethylation define short- and long-term enhancer regulation during cell fate specification.

Temporally discordant chromatin accessibility and DNA demethylation define short- and long-term enhancer regulation during cell fate specification.

MYCN as an oncogene in pediatric brain tumors.

MYCN, or N-Myc, is a member of the MYC family of transcription factors, which plays a key role in tumor formation by regulating genes involved in proliferation, differentiation, and apoptosis. MYCN is essential for neural development, especially for the appropriate growth and differentiation of neural progenitor cells, and its aberrant expression contributes to tumorigenesis. Gene amplification and mutations of this gene have been observed in a wide variety of cancer types, particularly in pediatric brain and non-brain tumors, such as neuroblastoma. Previous studies have provided extensive insights into the complex regulatory network of this transcription factor. Additionally, the presence of MYCN alterations in patient tumors serve as a key factor for risk stratification, as it correlates with poorer outcomes, and presents a significant challenge for treatment. Despite its clinical significance, therapeutic targeting of MYCN is challenging due to its structure, nuclear localization, and complex regulatory pathways. Efforts to target MYCN have focused on destabilizing the protein, modulating epigenetic mechanisms, and disrupting its transcriptional network. This review explores the role of MYCN in different subtypes of pediatric brain tumors and highlights novel ongoing therapeutic approaches. However, further research is necessary to develop more effective therapies and improve survival outcomes for patients with MYCN-driven tumor.

Biophysical-Inspired Interpenetrated Fibrillar and Reticular Collagen Scaffold with Vascular Endothelial Cell Membrane Incorporation for Guided In Situ Spleen Tissue Regeneration.

The spleen's complex structure and limited regenerative ability hinder its regrowth at the site of injure, affecting patient quality of life and risk severe complications. The spleen's stroma primarily consists of reticular and fibrillar collagen, supporting its microvascular network. Inspired by such biophysical environment, this work develops an inducible scaffold featuring an interpenetrating network structure of fibrous and reticular collagen, which is loaded with vascular endothelial cell membranes to facilitate in situ regeneration. The regenerated parenchyma includes red pulp, white pulp, and a vascular system. The scaffold effectively reduces oxidative stress at the injury site, recruits cells to degrade the scaffold, and promotes tissue integration, thereby accelerating spleen regeneration. Additionally, the regenerated tissue compensates for the spleen's functions, enhancing its ability to clear abnormal red blood cells and platelets. Proteomics and RNA sequencing analyses reveal that the scaffold induced the upregulation of key pathways, including the Wnt signalling pathway, Statin pathway, and amino acid metabolism pathway. This activation mobilizes splenic cells metabolism, enhances immune cell activity, and facilitates the remodeling of the extracellular matrix. Moreover, the incorporated cell membrane components promote splenic blood vessels regeneration by upregulating the neural crest cell differentiation pathway within the tissue.

Abstract 114: Unraveling the origin of Ewing sarcoma using zebrafish transgenic models

Abstract Ewing sarcoma (ES) is a pediatric cancer of bones and soft tissues with enigmatic origin. Ewing sarcoma cells are characterized by the presence of a driver fusion oncogene, most frequently EWSR1-FLI1. Previous reports have suggested that bone-marrow mesenchyme or/and neural crest cells may serve as potential cells of origin for Ewing sarcoma. These hypotheses have never been tested in vivo, largely due to the absence of a representative mouse model as the EWSR1-FLI1 fusion causes severe developmental toxicity in most cell types. To address these questions, we developed a stable zebrafish transgenic model enabling tissue-specific expression of the human EWSR1-FLI1 oncofusion in neural crest cells (Vasileva et al., 2024). Using this model, we demonstrated that expression of human EWSR1-FLI1 oncofusion in neural crest cells can lead to their transformation and the development of tumors in vivo. Single-cell analysis of tumor initiation shows that EWSR1::FLI1 reprograms neural crest-derived cells to a mesoderm-like state, strikingly resulting in ectopic fins formation throughout the body. EWSR1-FLI1 hindered the normal differentiation of neural crest cells into glial and neuronal lineages. Instead, EWSR1-FLI1 strongly reprogrammed neural crest cells by hijacking developmental enhancers and upregulating the expression of mesodermal regulators, including the key mesodermal regulator tbxta (Brachyury or T) transcription factor. tbxta/TBXT expression was maintained in subset of zebrafish and human Ewing sarcomas. Our model provides a mechanism by which a neural crest cell lineage can be transformed to Ewing sarcoma, a malignancy with predominant mesenchymal features. Taken together, these findings show how a single mutation profoundly alters embryonic cell fate decisions reprogramming neural crest cells to a mesoderm-like state to initiate a devastating childhood cancer. Citation Format: Elena Vasileva, Claire Arata, Gage Crump, James Amatruda. Unraveling the origin of Ewing sarcoma using zebrafish transgenic models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 114.

Magnesium-L-threonate Ameliorates Cognitive Deficit by Attenuating Adult Hippocampal Neurogenesis Impairment in a Mouse Model of Alzheimer's Disease.

Impaired adult hippocampal neurogenesis is a key pathological mechanism contributing to memory deficits in Alzheimer's disease (AD). Recent studies have shown that elevating magnesium levels promotes neurogenesis by enhancing the neuronal differentiation of adult neural progenitor cells in vitro. Therefore, this in vivo study aims to determine if magnesium-L-threonate (MgT) can ameliorate cognitive deficit of AD mice by attenuating adult hippocampal neurogenesis impairment and to reveal the underlying mechanisms. APPswe/PS1dE9 mice were treated with different doses of MgT and ERK inhibitor PD0325901. The memory ability of each mouse was recorded by Morris Water Maze test. After cognitive test, hippocampus tissues were collected to measure the proportion of BrdU/doublecortin double-labeled cells using the flow cytometry test and assess the expression of doublecortin using PCR and Western blot. Furthermore, the activations of CREB, ERK, P38 and JNK were measured by Western blot to identify the involved mechanisms. The cognitive test confirmed that MgT treatment attenuated the memory impairment of APPswe/PS1dE9 mice. Flow cytometry test showed that Brdu/doublecortin labeled newborn neurons gradually increased following MgT administration. In line with the flow cytometry results, Western blot and PCR confirmed that MgT administration significantly increased doublecortin expression levels. Furthermore, the ratios of p-ERK/ERK and p-CREB/CREB increased with MgT elevation. In addition, these effects of MgT treatment were markedly reversed by PD0325901 supplementation. In conclusion, MgT treatment improved cognitive decline by ameliorating adult hippocampal neurogenesis impairment in this AD model, possibly via ERK/CREB activation.

HOXD1 regulates neural crest cells differentiation and polycerate development in sheep

The polycerate trait in sheep is a complex phenotype regulated by polygenes. However, the mechanism behind multi-horned traits development and growth remains unclear. In this study, neural crest cells (NCCs) were isolated from mouse embryos, and the HOXD1 (Homeobox D1) gene was overexpressed in these cells to identify its function. Transcriptome analysis was performed to explore the key signaling pathway involved in forming the multi-horned traits in sheep. The results showed that the HOXD1 induced epithelial-to-mesenchymal transition (EMT) in mouse neural crest primary cells, affecting their migration but without significantly influencing proliferation. Furthermore, signaling pathway analysis suggested that HOXD1 may inhibit NCC proliferation by modulating Wnt rather than TGF-β signaling. Transcriptome analysis revealed that the HOXD1 gene affected the extracellular matrix of CXC family regulatory cells and promoted NCC differentiation. These findings provide a theoretical basis for further investigation into the regulation of multi-horned traits growth and development in sheep.

Electroacupuncture Promotes the Proliferation and Differentiation of Enteric Neural Precursor Cells via the PTEN/PI3K/Akt/mTOR Signaling Pathway in Diabetic Mice.

Enteric neuronal loss significantly contributes to gastrointestinal (GI) motility disorders. Electroacupuncture (EA) can promote the regeneration of lost enteric neurons in diabetic mice, but its mechanisms are not fully understood. Nestin+/Ngfr+ cells can function as enteric neural precursor cells (ENPCs) to proliferate and differentiate into enteric neurons in adult mice. However, EA's effects on ENPCs remain unknown. The study aimed to investigate whether EA reversed enteric neuronal loss via regulation of ENPCs and its molecular basis. The study utilized conventional C57BL/6J mice and ENPC-tracing transgenic mice. Streptozotocin-induced type 1 diabetic mouse, PI3K inhibitor, and PTEN inhibitor models were used. GI motility was evaluated by defecation frequency, fecal water content, and whole gut transit test. The alterations of enteric neurons, ENPCs, and PTEN/PI3K/Akt/mTOR signaling were detected by Western blot and immunofluorescence. EA increased defecation frequency and fecal water content, reduced whole gut transit time, and increased the number of enteric neurons. Notably, EA inhibited ENPC apoptosis and facilitated ENPC proliferation and differentiation with a preferential into ChAT enteric neurons. Additionally, PTEN was decreased and PI3K/Akt/mTOR signaling was activated with EA. However, LY294002 (PI3K inhibitor) inhibited EA's effects on ENPCs, while BpV(HOpic) (PTEN inhibitor) partially rescued these inhibitory effects. EA alleviates diabetic enteric neuropathy by regulating ENPC dynamics through the PTEN/PI3K/Akt/mTOR signaling pathway. Notably, EA-mediated anti-apoptotic and pro-proliferative effects on ENPCs, and their preferential cholinergic differentiation establish EA as a multimodal therapy that bridges neuromodulation with precursor cell biology, offering an alternative strategy for GI motility disorders.

Identification of lens-regulated genes driving anterior eye development.

Identification of lens-regulated genes driving anterior eye development.

Human neuron chimeric mice reveal impairment of DVL-1-mediated neuronal migration by sevoflurane and potential treatment by rTMS

,Whether early exposure to general anesthetics hurts human brain development is still under discussion. Animal studies have documented multiple neurotoxicities of repeated/prolonged exposure to sevoflurane (Sev, a commonly used pediatric anesthetic) at the neonatal stage. Its effects on human neural development remain elusive. Here, by investigating neural progenitor cells derived from two human embryonic stem cell lines, human cerebral organoids and human neuronal chimeric mice, we found that, although Sev inhibits neuronal differentiation and synaptogenesis of human neural progenitor cells in vitro, it only inhibits human neuronal migration in vivo. Chemogenetic activation of human neurons rescued the defects of cell migration and social dysfunction of Sev-pretreated human neuronal chimeric mice. Mechanistically, Sev inhibits DVL-1/Ca2+ signaling and multiple cell migration-related genes. Overexpressing DVL-1 enhanced the Ca2+ response, neuronal migration and social function of Sev-pretreated chimeric mice. Furthermore, specific modulation of human neurons by high-frequency transcranial magnetic stimulation not only activated DVL-1/Ca2+ signaling but also improved human neuronal migration and social function in chimeric mice. Our data demonstrate that early Sev exposure is toxic to human neuronal migration via inhibiting DVL-1 signaling and that transcranial magnetic stimulation could be potentially therapeutic.

Peripheral nerve regeneration with 3D printed bionic double-network conductive scaffold based on GelMA/chitosan/polypyrrole.

Peripheral nerve regeneration with 3D printed bionic double-network conductive scaffold based on GelMA/chitosan/polypyrrole.

Enhanced differentiation of neural progenitor cells in Alzheimer’s disease into vulnerable immature neurons

Enhanced differentiation of neural progenitor cells in Alzheimer’s disease into vulnerable immature neurons

Magnetically driven wireless implantable interface polarization-enhanced triboelectric nanogenerator for promoting neural cell differentiation

Magnetically driven wireless implantable interface polarization-enhanced triboelectric nanogenerator for promoting neural cell differentiation

Development of NIR photocleavable nanoparticles with BDNF for vestibular neuron regeneration

Among nanoparticle platforms, light or photoresponsive nanoparticles have emerged as a promising drug delivery strategy with spatiotemporal control while minimizing off-target effects. The characteristic absorption spectrum of the photoresponsive moiety dictates the wavelength of light needed to activate bond cleavage. However, the low tissue penetration depth limit and short-wavelength ultraviolet (UV) cellular toxicity are considered disadvantageous. This study developed a vestibular ganglion neuron organoid as a model for vestibulopathy. UV and near-infrared (NIR) radiation targeted the inner ear and neural cells, followed by toxicity evaluation. A significantly smaller toxicity of NIR light was confirmed. The photocleavage release of brain-derived neurotrophic factor (BDNF) was used by applying NIR wavelength. The results indicate that polyethylene glycol octamethylene diamine derivative conjugated with leucomethylene blue with an ethanolamine linker nanoparticle can be effectively disassembled and release BDNF when using the 808 nm laser as a trigger. The findings of the cytotoxicity assay suggest that photocleavable nanoparticles (PCNs) and laser irradiation are safe and biocompatible for human-derived and neural progenitor types of cells. Phototriggered BDNF release by NIR laser supported the growth and differentiation of human neural progenitor cells in culture. In addition, the vestibulopathy organoid exhibited a significant regenerative effect. This study harnesses the full potential of NIR laser PCNs to treat vestibular neuropathies.Graphical abstract

Mechanically Flexible Polymeric Nanoneedle Arrays for Promoting Differentiation and Functional Activity of Neural Progenitor Cells

Mechanically Flexible Polymeric Nanoneedle Arrays for Promoting Differentiation and Functional Activity of Neural Progenitor Cells

Human stem cell model of neural crest cell differentiation reveals a requirement of SF3B4 in survival, maintenance, and differentiation.

In vitro modeling is a powerful approach to investigate the pathomechanisms driving human congenital conditions. Here, we use human embryonic stem cells (hESCs) to model Nager and Rodriguez syndromes, two craniofacial conditions characterized by hypoplastic neural crest-derived craniofacial bones, caused by pathogenic variants of SF3B4, a core component of the spliceosome. We observed that siRNA-mediated knockdown of SF3B4 interferes with the production of hESC-derived neural crest cells, as seen by a marked reduction in neural crest gene expression. This phenotype is associated with an increase in neural crest cell apoptosis and premature neuronal differentiation. Altogether, these results point to a role of SF3B4 in neural crest cell survival, maintenance, and differentiation. We propose that the dysregulation of these processes may contribute to Nager/Rodriguez syndrome-associated craniofacial defects.