Frontiers in Cell and Developmental Biology最新文献

The remodeling of synapses in the hippocampus is intricately linked to processes of learning and memory. Research indicates that high-intensity interval training (HIIT) enhances cognitive functions reliant on the hippocampus in mice, although the specific receptor-mediated molecular pathways involved are not fully elucidated. Lactate, which is produced in significant amounts during HIIT, may function as a signaling agent in the brain through the lactate receptor G protein-coupled receptor 81 (GPR81), classified as a Gi-type G protein-coupled receptor. This investigation focused on the lactate/GPR81 pathway's contribution to synaptic remodeling in the hippocampus induced by HIIT and examined its downstream signaling characteristics. In vivo results demonstrated that HIIT led to an increase in dendritic spine density and presynaptic vesicle density, enhancing learning and memory; however, these structural and cognitive improvements were negated by the knockdown of GPR81 in the hippocampus. In vitro experiments with Neuro-2a (N2a) cells, when treated with a GPR81 agonist alongside an adenyl cyclase (AC) agonist, a phospholipase C (PLC) inhibitor, and an extracellular signal-regulated kinase 1/2 (ERK1/2) inhibitor, revealed that GPR81 activation resulted in elevated ERK1/2 phosphorylation and increased levels of proteins associated with synaptic remodeling. Further pharmacological interventions reinforced a dual downstream signaling mechanism that involves the inhibition of the AC pathway and the activation of the PLC pathway, both of which converge on ERK1/2. Overall, these results suggest that the lactate/GPR81 pathway is essential for the critical aspects of HIIT-induced synaptic remodeling in the hippocampus and the enhancement of memory, supporting a GPR81-dependent dual-branch model that converges on ERK1/2 in a simplified in vitro context.

Atrial fibrillation (AF) is the most common type of arrhythmia encountered in the clinical setting, and its occurrence is influenced by various factors, particularly aging. Senescence of atrial myocytes plays an important role in the development of AF, although the precise mechanisms underlying this association remain unclear. This review explores the pivotal role of atrial myocyte senescence in AF pathogenesis, moving beyond chronological age. It provides evidence that aging creates a pro-arrhythmic substrate via three interconnected mechanisms: 1) inflammatory activation (mitochondrial ROS, NLRP3, and SASP), 2) dysregulated calcium handling (RyR2 and SERCA2), and 3) cell cycle disruption (p16, p21, and p53). These pathways, compounded by epigenetic changes and SIRT1/mTOR signaling dysregulation, drive the electrical and structural remodeling that triggers and sustains AF. The review highlights promising therapeutic targets such as SIRT1 activators and NLRP3 inhibitors, proposing an integrated "senescence-AF axis" model, while identifying key research gaps in cell-type specificity and clinical translation. This comprehensive review outlines current progress in research in this area and future research directions and provides valuable references for forthcoming studies.

Introduction: Acute promyelocytic leukemia (APL) is a distinct subtype of acute myeloid leukemia (AML) with unique clinical features. Flow cytometry (FCM) immunophenotyping analysis is crucial for accurate diagnosis and prognostic stratification. This study aims to explore the association between specific immune phenotype markers in APL patients and overall survival (OS).

Methods: In this retrospective cohort study, immunophenotypic data from 72 APL patients were analyzed by FCM. Continuous and categorical variables are presented as mean ± standard deviation and frequency (percentage), respectively. Group comparisons were performed using ANOVA and Chi-square tests. Cox proportional hazards models were used to identify prognostic factors for OS, with results expressed as hazard ratios (HRs) and 95% confidence intervals (CIs). Kaplan-Meier survival analysis was employed to assess the impact of CD56, CD2, CD34, and CD200 expression on OS. Subgroup analyses were conducted based on age, gender, white blood cell count (WBC), and disseminated intravascular coagulation (DIC).

Results: The baseline age (p = 0.513) and gender (p = 0.881) were comparable across different PML-RARα isoform groups. Compared to non-APL AML, APL blasts were characterized by significantly higher expression of CD33, CD13, CD9, and MPO (all p < 0.05), and lower expression of CD7, CD34, CD56, CD38, CD200, and HLA-DR (all p < 0.001). The PML-RARα (S-type) group showed relatively higher expression of CD34, CD2, and CD200 than the L-type group. Univariate Cox analysis revealed that expression of CD34, CD2, CD56, and CD200 were all significantly associated with poorer OS. After multivariate adjustment, CD2 (adjusted HR = 1.04, 95% CI: 1.01-1.07, p = 0.004) and CD200 (adjusted HR = 1.04, 95% CI: 1.01-1.06, p = 0.009) remained independent adverse prognostic factors. Subgroup analysis confirmed that the negative prognostic impact of CD2 and CD200 expression was consistent across different patient subgroups.

Conclusion: Compared with non-APL-AML patients, APL patients (PML-RARα (S-type) and PML-RARα (L-type)) exhibit unique immunophenotypic changes. The expression frequencies of CD56, CD2, CD34, and CD200 in leukemia cells are significantly correlated with the OS of APL patients, and the high expression of these indicators before treatment may be an adverse prognostic factor for APL patients.

Background: Glioblastoma (GBM) is an aggressive malignancy of the central nervous system characterized by rapid progression, therapeutic resistance, and poor prognosis. Epithelial-mesenchymal transition (EMT) contributes to tumor plasticity and immune remodeling in GBM. Identification of EMT-driving genes (EDGs) with prognostic and therapeutic relevance may provide insights into disease progression and precision management. This study aimed to systematically identify prognostic EDGs and to construct a robust EMT-based prognostic model for GBM.

Methods: Univariate Cox regression analyses were performed across five GBM cohorts (TCGA, CGGA-693, CGGA-325, GSE83300, and GSE74187) to rank genes according to hazard ratios, followed by Gene Set Enrichment Analysis (GSEA), which identified EMT as the pathway most strongly associated with adverse survival. EMT-related genes from MSigDB and dbEMT2.0 were intersected with TCGA-derived prognostic genes to obtain 145 EDGs. An EMT-related prognostic signature was generated using LASSO Cox regression and validated in independent datasets. Functional analyses, including Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), weighted gene co-expression network analysis (WGCNA), and GSEA, elucidated biological processes associated with the risk signature. Immune infiltration analyses (ESTIMATE, CIBERSORT) and drug sensitivity analyses characterized the tumor microenvironment and therapeutic response. Random Forest analysis and in vitro assays identified and validated GJB2 as a key mediator of GBM progression.

Results: A total of 145 EDGs were identified by integrating survival-associated genes from TCGA with EMT-related genes from MSigDB and dbEMT2.0. An EMT-related prognostic signature was developed and validated across five GBM cohorts. The risk score stratified patients into high- and low-risk groups with significantly different survival outcomes and remained an independent prognostic factor in multivariate Cox analyses. A nomogram integrating the risk score with age, IDH mutation status, and MGMT promoter methylation demonstrated strong predictive performance. Immune profiling revealed that the high-risk group exhibited an "immune-inflamed yet immunosuppressed" phenotype characterized by elevated macrophage and regulatory T-cell infiltration. Drug sensitivity analyses suggested that high-risk GBM may respond better to paclitaxel and tamoxifen. Random Forest modeling and in vitro experiments identified GJB2 as an oncogenic driver that promotes GBM cell proliferation and migration.

Conclusion: Our findings provide a clinically applicable EMT-based prognostic framework that links transcriptional plasticity to patient outcomes in GBM and identify GJB2 as a promising therapeutic target.

Malignant melanoma is an aggressive skin malignancy with a complex molecular landscape and limited treatment durability in advanced stages. Aberrations in the MAPK pathway-most notably BRAF and NRAS mutations-have catalyzed the development of targeted therapies, particularly BRAF/MEK inhibitors, which have transformed outcomes in BRAF-mutant melanoma. However, resistance remains prevalent, driven by MAPK reactivation, epigenetic rewiring, and tumor microenvironmental feedback. In NRAS-mutant subtypes, MEK inhibition, CDK4/6 blockade, and immune checkpoint inhibition offer partial efficacy, yet monotherapies fail to achieve sustained responses. Emerging strategies focus on combinatorial regimens targeting RAF-MEK-ERK and PI3K-AKT axes, alongside immunotherapeutic integration. Rarer alterations in KIT and RTKs also define actionable subsets. This review synthesizes recent mechanistic insights and therapeutic advances in mutation-driven melanoma, highlighting the promise of biomarker-guided combination strategies and signaling crosstalk disruption as the next frontier in precision oncology.

Background: Autophagy dysregulation plays an important role in the development and progression of lupus nephritis (LN). However, the key autophagy-related genes involved in LN and their underlying cellular mechanisms remain unclear. This study aims to systematically explore the autophagy-related molecular signatures of LN and to elucidate the relevant mechanisms.

Methods: Transcriptomic data from LN and control kidney tissues were analyzed to identify differentially expressed genes (DEGs), followed by KEGG, GSEA, and GSVA enrichment. Autophagy-related DEGs (ARDEGs) were obtained by intersecting DEGs with autophagy gene sets. Hub genes were screened using PPI network analysis, cytoHubba algorithms, and WGCNA. Diagnostic performance was assessed by ROC curves and a nomogram. Single-cell datasets and qRT-PCR, pathology, TEM, and immunohistochemistry were used for validation. Functional assays were conducted in CIHP-1 podocytes with stable EGFR overexpression.

Results: A total of 445 ARDEGs were identified, enriched in autophagy, PI3K-Akt/mTOR, and MAPK pathways. Eleven hub genes were obtained, among which EGFR and RAF1 showed strong diagnostic value (AUC >0.90) and correlations with immune infiltration. Single-cell and experimental validation revealed elevated EGFR expression in LN. EGFR-overexpressing podocytes exhibited increased MDC fluorescence by flow cytometry, autophagosome accumulation by TEM, and a significant increase in LC3-positive puncta by confocal microscopy.

Conclusion: EGFR is a key regulatory factor related to autophagy in LN. The excessive activation of EGFR affects the autophagy of LN podocytes, providing new mechanistic insights and potential therapeutic targets for LN.

Death or dysfunction of retinal pigment epithelium (RPE) cells occurs in age-related macular degeneration (AMD) and certain inherited retinal dystrophies (IRDs). Induced-pluripotent stem cell (iPSC) derived-RPE have been used in early-stage clinical trials to treat AMD and IRDs by injecting them as a cell suspension or monolayers. While RPE transplant shows therapeutic potential, issues ranging from failure to repopulate the entire treatment area, clumping and monolayer folding, and a foreign body response to the support have been reported. We've shown that RPE can be grown on high concentration (>30 mg/mL) degradable fibrin hydrogels, and that cell free fibrin hydrogels implanted in the subretinal space degrade without causing inflammation. Here we describe manufacture and surgical implantation of degradable fibrin hydrogels carrying iPSC-RPE into a porcine model of geographic atrophy (GA). Large (15.25 × 58.42 × 0.2 mm) fibrin gel blanks were produced by injection molding, and iPSC-RPE were grown on their surface. Using a mechanical punch, the blank was subdivided into 1.5 × 5.0 × 0.2 mm doses, which fit a custom tool used for storage and surgical placement. Following aseptic packaging, RPE and gels were stable at 37 °C for at least 7 weeks. When transplanted into a pig model of GA, the fibrin scaffold degraded in <1 month and the iPSC-RPE provided partial rescue from GA as assessed by preservation of photoreceptors and blood flow in the choriocapillaris. We conclude that iPSC-RPE delivered on degradable fibrin hydrogels represent a potentially safe and effective approach to RPE transplantation.

Retinal ganglion cells (RGCs) are the output neurons of the retina, responsible for transmitting visual signals to the brain through the optic nerve. Their long axons, high metabolic demand, and the variable environments they transit make them particularly vulnerable to neurodegenerative insults in optic neuropathies. These insults include oxidative stress, excitotoxicity, and inflammatory damage, either within the neuroretina or within the optic nerve, and are thought to drive disease etiology. RGC-related vision loss is the primary presenting concern in many optic neuropathies including glaucoma and autoimmune demyelinating diseases such as multiple sclerosis MS-related optic neuritis (ON) is a result of immune-mediated damage to the myelinated optic nerve, a process not fully recapitulated in current in vitro organoid models. For instance, 3D organoid models offer improved architectural context, but they lack crucial cell types and sufficient anatomic complexity to mimic the in vivo environment. Further, widespread use of animal-derived reagents in these systems can introduce significant phenotype variability posing a major barrier to translational research. To address these challenges, retinofugal assembloid models have emerged. These models combine retinal and brain organoids to recapitulate the in vivo visual pathway, supporting RGC survival, RGC axonal extension and pathfinding, incorporation of additional glial cell types, and provide sufficient complexity. Here, we describe xenobiotic-free protocols for generating retinal and oligodendrocyte-rich cortical organoids and their fusion into assembloids to more accurately model RGC physiology. We discuss the advantages, limitations, and future applications of these systems in studying neuroinflammation and demyelination in a human-relevant context.

Introduction: Adipose-derived stem cells (ASCs) hold significant promises for various regenerative approaches, necessitating the production of a substantial quantity of in vitro expanded ASCs for clinical applications. While ASC expansion is traditionally performed in tissue culture polystyrene (TCP) flasks, the Quantum Cell Expansion System, a hollow fiber bioreactor (HFB), offers an automated and closed system for cell expansion, presenting advantages over manual culture methods. In this study, we compared ASC cultures from a HFB system with traditional TCP flasks, focusing on immunophenotypes.

Methods: ASCs from three donors were cultured and underwent equivalent population doublings in both systems. The cell number was counted to compare the growth rate. Furthermore, the individual expressions of 15 surface markers and their co-expression of 5 (CD73, CD90, CD105, CD166, and CD201) and 8 epitopes (CD34, CD36, CD146, CD248, CD271, CD274, and Stro-1) were analyzed by using multicolor flow cytometry.

Results: ASCs expanded in the HFB and TCP system showed a comparable growth rate. Except for a significant downregulation of CD201 in HFB (p = 0.008), other surface marker expression profiles were largely comparable between HFB and TCP, with no statistically significant differences observed. While both systems met ISCT criteria for ASC identity, the HFB supported a broader diversity of clonal lineages (greater immunophenotypical heterogeneity), particularly by preserving both CD274-positive and -negative subpopulations. In contrast, TCP culture selectively favored CD201+ and CD274+ clones, indicating environment-driven shifts in subpopulation dynamics.

Conclusion: The expansion method significantly influences the phenotypic composition of ASCs. HFB systems offer a promising alternative for large-scale ASC manufacturing by better maintaining subpopulation diversity. These findings emphasize the need for functional validation of ASC subtypes and careful consideration of expansion platforms in clinical-grade cell production.

The field of epitranscriptomics discovered N6-methyladenosine (m6A) modifications, which function as fundamental elements that control RNA metabolism properties that powerfully affect cancer biology. This review examines the way m6A modifications shape RNA stability while regulating translation, together with their eraser and reader proteins. We demonstrate that m6A modifications guide oncogene and tumor suppressor transcript outcomes, which promote tumor growth, metastasis, and therapeutic resistance. The regulatory function of m6A depends significantly on its relationship with ncRNAs that mainly include miRNAs, lncRNAs, and circRNAs. The review examines the effects of m6A on ncRNA production, stability, export, and degradation, as well as the regulation of m6A protein expression by ncRNAs, highlighting intricate reciprocal feedback loops that drive cancer progression. The interplay between m6A RNA modifications and ncRNAs provides emerging evidence on how they collectively influence the tumor microenvironment, modulate immune system responses, and contribute to resistance. Harnessing ncRNA-m6A interactions for managing drug resistance offers promising therapeutic avenues. However, advancing our understanding of the context-specific roles of m6A modifications and translating these insights into clinical applications remains a significant challenge. This review synthesizes recent findings on ncRNA-m6A crosstalk to lay the groundwork for developing epitranscriptomic strategies in precision oncology.