Frontiers in Cell and Developmental Biology最新文献

Lysosome-related organelles (LROs) encompass specialized intracellular compartments that share features with lysosomes while fulfilling distinct physiological roles, with melanosomes representing the best-studied example. Melanosome biogenesis relies on coordinated trafficking, sorting, and membrane remodeling mechanisms that diverge from the canonical endolysosomal pathways. These organelles ultimately serve as the primary sites of melanin synthesis and deposition. In the skin, melanin is produced by melanocytes and transferred to keratinocytes, where it achieves its essential photoprotective role. Melanin is a remarkably diverse and ancient polymer, with eumelanin, pheomelanin, and neuromelanin constituting the major mammalian forms. Understanding melanin biology also requires tracing the origins of melanocytes, which were once thought to derive exclusively from the neural crest but are now known to arise from multiple embryonic lineages. This expanded view of melanocyte ontogeny has revealed unexpected pigment cell populations in several internal organs. Beyond these developmental aspects, melanin performs multifaceted physiological functions that extend far beyond photoprotection of the skin. Here, we discuss the current knowledge on the origin of melanosomes from endosomal precursors, the transfer of melanin from melanocytes to keratinocytes, and its fate in these recipient cells within the epidermis. Additionally, the intriguing mysteries surrounding melanosomes in the retinal pigment epithelium are addressed, as well as the broader diversity, origins, and physiological roles of melanin in other cell types. Taken together, these perspectives highlight the melanosome as both a model LRO and an organellar hub for deciphering melanin diversity, cellular origins, and the wide-ranging physiological roles of this pigment in vertebrate biology.

Objective: This study aims to integrate metabolomics and transcriptomics data to investigate the protective effects of umbilical cord mesenchymal stem cells (UC-MSCs) on obstetric deep vein thrombosis (DVT) and to elucidate the underlying molecular mechanisms.

Methods: A pregnant rat model of DVT was established using the inferior vena cava (IVC) stenosis method. The protective effects of UC-MSCs on DVT and endothelial cell injury were evaluated both in vivo and in vitro. Transcriptomic and metabolomic analyses were performed to identify differentially expressed genes (DEGs) and differentially abundant metabolites (DMs) in IVC tissues from DVT rats and those treated with UC-MSCs. Correlation analysis was conducted to associate relevant metabolites and RNAs. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis was applied to DEGs and DMs to identify significantly involved pathways. The mRNA-transcription factor regulatory network was constructed using Cytoscape software. Receiver operating characteristic (ROC) curves for immune regulatory genes and DEGs were generated with the R package pROC. The mMCP-counter algorithm was used to assess the distribution and abundance of immune cell subsets.

Results: The rat DVT model was established using the IVC stenosis method. Administration of UC-MSCs reduced thrombus burden, promoted angiogenesis, and mitigated hydrogen peroxide-induced endothelial injury in the DVT model. Integrated transcriptomic and metabolomic analyses revealed significant correlations between four key metabolites-pyridine, nicotinamide, L-phenylalanine, and L-leucine-and 24 interacting genes. These metabolites served as critical nodes within the regulatory network. KEGG enrichment analysis indicated that pathways such as amino acid biosynthesis and phenylalanine metabolism are implicated in the therapeutic effects of UC-MSCs on pregnancy-related DVT. Notably, the hub gene Got2 was associated with amino acid biosynthesis, while both Got2 and Maoa were involved in phenylalanine metabolism. Furthermore, seven immune-regulatory genes, including Gaa and Tlr2, demonstrated significant classification performance (area under the curve [AUC] > 0.8) in ROC curve analysis.

Conclusion: This study elucidates the protective mechanisms of UC-MSCs in the treatment of DVT in pregnant rats induced by the inferior vena cava stenosis model. These findings provide a scientific basis for the further evaluation and development of UC-MSCs-based therapeutic strategies for DVT during pregnancy.

Polycystin-1 (PC-1), a transmembrane protein expressed on cell membranes, plays a vital role in cell signaling and intercellular adhesion. Existing studies have shown that PC-1 plays a pivotal role in bone remodeling and that PC-1 deficiency results in disrupted bone remodeling, which markedly affects bone mass and skeletal development. This review describes the molecular structure and biological function of PC-1 and analyzes the mechanism by which it maintains bone homeostasis and regulates osteoblast and osteoclast activity. Particular emphasis is placed on the role of PC-1 in mechanical force-triggered bone remodeling and its interaction with the transcriptional co-activator tafazzin. Moreover, this review outlines the potential applications of PC-1 in treating skeletal diseases, such as osteoporosis, fractures, and premature closure of cranial sutures, thereby providing a theoretical basis for future research.

Mitochondria are central organelles in regulating apoptosis, cellular metabolism, metabolite biosynthesis, energy production, and overall cellular homeostasis. Over the past years, abundant evidence has shown that mitochondrial dysfunction and the resulting metabolic reprogramming profoundly influence key hallmarks of tumor development, including initiation, progression, angiogenesis, and metastasis, playing a role also in therapeutic resistance. Consequently, mitochondria have emerged as a promising target for anticancer therapy. Beyond well-known mutational abnormalities in the mitochondrial genome, recent studies indicate that altered mitochondrial epigenetic mechanisms could also contribute to cancer etiology. In the current review, we present a brief, up-to-date overview of the literature on mitochondrial epigenetic regulation in cancer. We will focus on the main characterized mitoepigenetic mechanisms, namely mitochondrial DNA (mtDNA) methylation and activity of mtDNA-encoded non-coding RNAs. We also consider bidirectional epigenetic crosstalk between the nucleus and mitochondria, whereby metabolites and signaling pathways coordinate chromatin states and mitochondrial function. Collectively, available evidence links mitoepigenetic alterations to tumor progression and pharmacoresistance, nominating these pathways as tractable targets for pharmacological intervention.

High-intensity interval training (HIIT) improves cardiovascular performance, but the mechanisms remain incompletely delineated. We investigated whether HIIT improves left-ventricular (LV) remodeling after myocardial infarction (MI) in adult mice. Animals underwent permanent coronary ligation or sham surgery and were randomized to Control, HIIT-only, Sham, MI-only, and MI + HIIT. HIIT comprised 15 treadmill bouts (60 s at 90%-110% maximal running speed followed by 30 s rest), 3 days/week for 6 weeks. Baseline echocardiography 1 week after MI confirmed comparable LV dysfunction in MI-only and MI + HIIT groups. After intervention, the MI + HIIT group showed higher running capacity, improved LV ejection fraction (26.18% vs. 16.19%; p < 0.01) and fractional shortening (12.24% vs. 7.41%; p < 0.01), and less LV dilation versus MI-only. Myocardial fibrosis was reduced in MI + HIIT (8.85% vs. 13.17%; p < 0.01), consistent with physiological remodeling. 5-ethynyl-2'-deoxyuridine (EdU) incorporation identified more DNA synthesis in MI + HIIT (1.71%) and HIIT-only (1.24%) hearts. Bulk RNA sequencing showed coordinated upregulation of contractile and metabolic pathways and downregulation of apoptosis and inflammatory signaling, aligning with improved cell-cycle activity and oxidative-metabolic efficiency. Collectively, HIIT enhanced exercise capacity and cardiac function, attenuated fibrosis, and reprogrammed cardiac gene expression toward pro-contractile and anti-inflammatory programs consistent with a cell-cycle-permissive state in a post-MI mouse model.

Osteoarthritis (OA) is a degenerative joint disease characterized by articular cartilage degradation, extracellular matrix breakdown, low-grade chronic inflammation, and pain. Its etiology is complex and treatment options are limited. In recent years, ferroptosis, a regulated form of cell death driven by iron-dependent lipid peroxidation, has gained significant attention in OA pathogenesis. Glutathione peroxidase 4(GPX4), serves as the central enzyme that halts lipid peroxidation and inhibits ferroptosis. Its expression and activity are altered in OA cartilage under pathological conditions, suggesting a crucial role for GPX4 in OA pathogenesis and treatment. This review summarizes the molecular characteristics and antioxidant functions of GPX4, evaluates experimental evidence linking GPX4 and ferroptosis in OA, outlines upstream and downstream molecular mechanisms regulating GPX4, and summarizes therapeutic strategies targeting GPX4, including pharmacological, gene, and combination therapies. It also discusses current research challenges and future directions. Finally, key pathways and strategic recommendations for translating GPX4 and ferroptosis research into clinical OA treatments are proposed.

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.