Frontiers in Cell and Developmental Biology最新文献

Introduction: Ganoderma lucidum is a fungus used in traditional Chinese medicine with high medicinal value and is also widely used in modern healthcare. Its spores are reported to contain antitumor and anti-inflammatory properties, among other biological benefits; however, the thick spore wall limits its bioavailability. Sporoderm-removed Ganoderma lucidum spores (RGLS) offer improved bioavailability. However, data on their safety in pregnant and lactating populations remain limited, highlighting the need for developmental and reproductive toxicity (DART) assessment. We aimed to evaluate the developmental and reproductive safety of RGLS to support its clinical application in maternal and perinatal populations.

Methods: Following ICH S5 (R3) guidelines, we conducted three non-clinical DART studies: embryo-fetal developmental (EFD) toxicity in rats, in vitro whole-embryo culture (WEC) in rabbits, and prenatal and postnatal toxicity (PPND) in rats. Female rats were administered RGLS (0.4, 1.2, and 4.0 g/kg/day) via oral gavage from gestation day (GD) 6 to GD17 (EFD) or to postnatal day (PND) 20. Rabbit embryos were cultured for 48 h in media containing 0.688, 0.963, and 1.238 mg/mL RGLS extract.

Results: Our results showed no maternal toxicity, embryotoxicity, or teratogenicity in rats, apart from reversible drug-mixed feces. The offspring showed no adverse effects on growth, neurodevelopment (Morris water maze), or fertility. Rabbit embryos exhibited normal morphology and organ development. The no-observed-adverse-effect level of RGLS was 4.0 g/kg, which was approximately 20 times the intended clinical dose.

Discussion: Overall, our study supports the safe use of RGLS in clinical applications for pregnant and lactating women, indicating that it can be added to a healthy diet.

Background: The cell - cell communication between macrophages and mesenchymal stromal/stem cells (MSCs) holds pivotal importance in the fracture healing process. Considering the intricate nature of the in vivo bone regeneration microenvironment, elucidating the changes in different macrophage subsets within this microenvironment, as well as the cell - cell communication between these subsets and MSCs, is essential for the differentiation, recruitment, and regulation of MSCs. This study was designed to investigate the interactions between diverse macrophage subsets and MSCs during the fracture healing period.

Methods: Single - cell sequencing was utilized to analyze the expression of Tspan4⁺, Lyve1⁺, and Mpeg1⁺ in macrophages during fracture healing, along with the cell - interaction signals with MSCs. It was demonstrated that the cell - interaction signal transduction might be linked to migrasomes. Scratch assays and transwell assays were carried out to assess the migration capacity of MSCs affected by exosomes and migrasomes derived from Tspan4⁺Mpeg1⁺ macrophages. Micro-CT and immunofluorescence techniques were employed to observe the impacts of exosomes and migrasomes from 100 μg/mL Tspan4⁺Mpeg1⁺ macrophages on femoral fracture healing in mice.

Results: Through single - cell sequencing, it was ascertained that macrophages highly expressed Tspan4 during the fracture healing process and could be categorized into Tspan4⁺Lyve1⁺ macrophages and Tspan4⁺Mpeg1⁺ macrophages. By means of cell - communication analysis, Tspan4⁺Lyve1⁺ macrophages and Tspan4⁺Mpeg1⁺ macrophages were proposed to interact with MSCs via Gas6 - Axl and IL1b - IL1r1, respectively. Collectively, macrophage-derived migrasomes convey IL-1β to MSCs to activate AMPK, thereby enhancing BMSC migration and likely osteogenic priming during fracture repair. These findings identify migrasomes as a previously underappreciated conduit in macrophage-BMSC crosstalk and suggest a vesicle-based strategy to improve fracture healing.

Background: Clear cell renal cell carcinoma (ccRCC) is the predominant subtype of kidney cancer. Its incidence and mortality rates remain consistently high, creating an urgent need to identify novel biomarkers and therapeutic targets. Necrosis by sodium overload (NECSO), mediated by the TRPM4 channel, represents a newly discovered form of cell death; however, its role in ccRCC remains unclear.

Methods: We performed a pan-cancer analysis of TRPM4 using TCGA data. GO, and KEGG enrichment analyses were employed to investigate TRPM4-associated functions and pathways in KIRC. Three machine learning algorithms (plsRcox, GBM, and CoxBoost) were integrated to identify 14 pivotal genes for constructing a comprehensive NECSO Score. TIME was assessed using CIBERSORT, xCell, and ESTIMATE algorithms. Finally, the biological functions of TRPM4 were validated in 769-P and A498 cells through in vitro experiments.

Results: Pan-cancer analysis revealed that TRPM4 was significantly downregulated in KIRC, and its high expression was associated with prolonged RFS. The NECSO Score, derived from the 14-gene signature, served as an independent protective prognostic factor. A high NECSO Score was correlated with an activated immune microenvironment, characterized by increased infiltration of CD8⁺ T cells and Th1 cells. In vitro assays confirmed that TRPM4 overexpression suppressed the proliferation, migration, and clonogenicity of ccRCC cells while promoting apoptosis. Furthermore, TRPM4 overexpression synergized with the sodium overload inducer Necrocide-1 (NC1) to enhance anti-tumor efficacy.

Conclusion: This study systematically unveils the tumor-suppressive role of TRPM4 in ccRCC and innovatively establishes the NECSO Score as a robust prognostic model. This score not only accurately predicts patient outcomes but also illuminates the potential link between sodium ion homeostasis and the tumor immune landscape. Targeting TRPM4 and NECSO may represent a promising therapeutic avenue for ccRCC.

Ferroptosis, a regulated form of cell death driven by iron-dependent lipid peroxidation, has emerged as a critical link between cellular senescence and Alzheimer's disease (AD). Senescent cells disrupt iron metabolism, promote peroxidation-prone lipid remodeling, and suppress antioxidant defenses, creating a pro-ferroptotic environment that accelerates neuronal degeneration. This review integrates recent mechanistic evidence demonstrating that these senescence-induced changes heighten ferroptotic susceptibility and drive AD pathology through pathways involving protein aggregation, autophagic failure, and inflammatory synaptic loss. Importantly, physical exercise has emerged as a pleiotropic intervention that counteracts these ferroptotic mechanisms at multiple levels. Exercise restores iron homeostasis, reprograms lipid metabolism to reduce peroxidation risk, reactivates antioxidant systems such as GPX4, enhances mitochondrial and autophagic function, and suppresses chronic neuroinflammation. Moreover, systemic adaptations through muscle, liver, and gut axes coordinate peripheral support for brain health. By targeting ferroptosis driven by cellular senescence, exercise not only halts downstream neurodegenerative cascades but also interrupts key upstream drivers of AD progression. These findings position ferroptosis as a therapeutic checkpoint linking aging biology to neurodegeneration and establish exercise as a mechanistically grounded strategy for AD prevention and intervention.

Purpose: To comprehensively evaluate the clinical utility, imaging performance, and safety of orally administered fluorescein angiography (oral FA) combined with an ultra-wide-field imaging system in the diagnosis and management of fundus disorders.

Methods: This prospective study enrolled 382 patients (676 eyes) aged 4-83 years, comprising 164 females and 218 males. All participants underwent oral FA after ingesting a weight-based dose of fluorescein sodium. Anonymized peak-phase images were independently graded by four retina specialists using a standardized three-parameter scoring system. Images were classified as high, moderate, or poor quality based on total scores. Circulation times (first appearance time, detailed visualization time, and optimal visualization time) and adverse events were systematically recorded. Statistical analyses assessed differences in image quality and timing across age groups and disease categories.

Results: Oral FA was successfully performed in all cases. Among 676 eyes, 662 (97.9%) were graded as high quality, 12 (1.8%) as moderate quality, and 2 (0.3%) as poor quality. Clinically useful images were obtained in 99.7% of cases. No significant differences in image quality or circulation times were observed across age groups. However, image quality was significantly higher in retinal degenerative diseases compared to retinal vascular diseases (P = 0.001), though both groups maintained diagnostically adequate scores. In addition, no significant differences in circulation times (first appearance time, detailed visualization time, and optimal visualization time) were observed among any disease groups. Mild adverse events (nausea, rash) occurred in only 2.1% of patients, with no severe reactions-even in six patients with prior intravenous FA (IVFA) allergy history.

Conclusion: Oral FA is a well-tolerated and clinically effective imaging modality that produces high-quality, diagnostically reliable angiograms across all age groups and multiple retinal disease categories. Its non-invasive nature, excellent safety profile, and ability to visualize peripheral pathology support its use as a practical and valuable alternative to conventional IVFA, particularly in pediatric, needle-phobic, or allergy-prone populations.

Triple-negative breast cancer (TNBC) is a highly aggressive subtype of breast cancer characterized by the absence of estrogen, progesterone, and HER2 receptor expression. This malignancy is often associated with a poor prognosis, early recurrence, and limited treatment options. The tumor microenvironment (TME) in TNBC plays a pivotal role in tumor progression, immune evasion, and therapeutic resistance. In recent years, an increasing body of evidence has highlighted the critical interactions between cancer cells and the components within the TME, including immune cells and soluble components. These interactions influence not only the biological behavior of the tumor but also its response to treatment. Exploring the complex interplay between tumor cells and immune components continues to inform the development of more effective therapeutic approaches. In this study, we provide a synopsis of advancements regarding the TME in TNBC. In light of different cellular compartments, we delineate multiscale interplays within the stroma-tumor symbiosis and highlight their antitumor functions and promising targeting strategies.

Objective: Chronic obstructive pulmonary disease (COPD) presents core pathological changes that current medications cannot reverse. Mesenchymal stromal cell (MSC) transplantation has shown therapeutic potential in preclinical studies; however, significant heterogeneity and inconsistency exist in animal experiments simulating key COPD pathologies (such as emphysema and inflammation) based on acute injury models. We aim to systematically evaluate the efficacy of MSC transplantation in animal models simulating COPD pathology through a meta-analysis and to explore the impact of key strategies such as administration routes and dosages on efficacy.

Methods: A systematic search was performed in PubMed, Web of Science, Embase, and Scopus databases (up to 1 July 2025) to identify randomized controlled trials (RCTs) involving MSC transplantation in animal models of simulated COPD pathology. Risk of bias was assessed using the SYRCLE tool, and meta-analysis was conducted using R software.

Results: A total of 40 studies were included. The meta-analysis revealed that MSC transplantation significantly improved alveolar structural damage compared to control groups (MLI: SMD = -2.84, 95% CI: 3.22 to -2.45), increased anti-inflammatory IL-10 levels (SMD = 6.54, 95% CI: 2.08-11.00), reduced pro-inflammatory TNF-α levels (SMD = -1.61, 95% CI: 2.72 to -0.5), and significantly inhibited pulmonary tissue cell apoptosis (SMD = -4.06, 95% CI: 5.71 to -2.41). Subgroup analysis showed that intratracheal transplantation was more effective than intravenous transplantation in improving MLI, enhancing IL-10 levels, and reducing apoptosis. Moreover, the therapeutic effects were dose-dependent, with higher doses (≥5 × 10⁶) generally yielding superior outcomes. Publication bias assessment for MLI suggested potential bias; however, the adjusted combined effect size remained statistically significant, confirming the robustness of the conclusion that MSCs significantly improve alveolar structure.

Conclusion: MSC transplantation exerts multiple therapeutic effects by alleviating emphysema, regulating inflammatory balance, and inhibiting cell apoptosis. The study further identifies intratracheal delivery and higher cell dosages as promising optimization strategies for MSC transplantation. These findings provide critical references for the standardized design of future preclinical studies and the selection of parameters for subsequent clinical trials, while the differences in disease progression between animal models and human conditions remain key factors to consider for future clinical translation.

Type 2 diabetes (T2D) is a complex metabolic disorder characterized by systemic insulin resistance and progressive deterioration of pancreatic β-cell function. Advances in single-cell transcriptomics, epigenomics, and spatial transcriptomics have delineated marked β-cell heterogeneity, revealing subpopulations with differential secretory capacity, stress resilience, and vulnerability to metabolic and immune-mediated insults. These high-resolution approaches have further identified disease-associated alterations in other islet endocrine cells, as well as in immune, stromal, and exocrine pancreatic compartments, highlighting the central role of intercellular signaling in T2D pathogenesis. Concurrently, microbiome research has elucidated mechanisms by which gut microbial composition and metabolic activity modulate glucose homeostasis and β-cell function through immunoregulatory pathways, maintenance of epithelial barrier integrity, and enteroendocrine signaling, notably via glucagon-like peptide-1 (GLP-1). Therapeutic strategies targeting the gut microbiota include conventional probiotics, prebiotics, and fecal microbiota transplantation, alongside emerging synthetic biology approaches employing genetically engineered probiotic strains to deliver bioactive molecules, including GLP-1, directly in the gut microenvironment. This review integrates current multi-omics and experimental evidence to provide a comprehensive framework for understanding β-cell molecular plasticity, microbiota-mediated metabolic regulation, and their intersection as potential therapeutic targets. Such integrative approaches offer prospects for the development of precision interventions aimed at preserving or restoring β-cell function in T2D.

In global terms, gastric cancer (GC) represents one of the most commonly occurring malignancies. It is positioned as the fifth most frequent cancer in terms of incidence and stands as the third primary contributor to cancer-related mortality. As per the latest global cancer report from 2020, there were approximately 1.1 million new cases of GC and about 800,000 new deaths in that year, making up 5.6% of new cases and 7.7% of deaths related to cancer. In recent years, as bioinformatics technology and high-throughput sequencing have advanced rapidly, our comprehension of the genetic and epigenetic alterations associated with GC has also progressed considerably. Among these alterations, RNA methylation, as one of the common modifications within RNA molecules, has been regarded as a key factor in the development and progression of GC. Research indicates that the dysregulation of RNA methylation influences GC development through various pathways. Therefore, understanding the pathogenic mechanisms of RNA methylation in GC is of great significance for the diagnosis, treatment and prognostic assessment of affected patients. In this review, we discuss various types of RNA methylation, including N6-methyladenosine (m6A), 5-methylcytosine (m5C), N7-methylguanosine (m7G), and N1-methyladenosine (m1A), and how they might affect the mechanism of GC. We also look at how RNA methylation impacts chemotherapy, targeted therapy, and immune resistance in gastric cancer, as well as the potential uses of RNA methylation in treating gastric cancer, setting the stage for more detailed research on RNA methylation in gastric cancer.

ANLN is a highly conserved actin-binding protein that plays a critical role in cytokinesis by interacting with key cytoskeletal components such as actin, myosin, and RhoA. Increasing evidence shows that ANLN is aberrantly overexpressed in various cancers, including lung, breast, and liver cancers, and that its elevated expression is associated with enhanced tumor cell proliferation, migration, and invasion. Because of its central involvement in tumorigenesis and disease progression, ANLN has emerged as a promising prognostic biomarker and potential therapeutic target. Recent studies have demonstrated that ANLN contributes to resistance to chemotherapy, targeted therapy, and immunotherapy through multiple molecular mechanisms. This review provides a systematic overview of the physiological functions of ANLN, its roles in cancer initiation and progression, and its regulatory mechanisms in treatment resistance, offering biological insights into precision oncology and potential strategies for overcoming therapeutic resistance in cancer.