Frontiers in Cell and Developmental Biology最新文献

Backgrounds: This study aimed to evaluate the efficacy and safety of mesenchymal stem cell (MSC) therapy for osteoarthritis (OA) through a systematic review and meta-analysis of randomized controlled trials (RCTs), focusing on patient-reported pain and functional outcomes.

Methods: A comprehensive literature search was conducted across multiple databases including PubMed, Embase, Web of Science, and Cochrane Library from inception to 1st October 2025. RCTs comparing intra-articular MSC injections with control interventions (placebo, hyaluronic acid, or other active treatments) in adult OA patients were included. Primary outcomes were changes in pain intensity measured by Visual Analog Scale (VAS) and functional improvement assessed by International Knee Documentation Committee (IKDC) score. Secondary outcomes included Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), Lequesne index, Lysholm score, and Tegner activity scale. Data were pooled using random-effects models and expressed as mean differences (MD) with 95% confidence intervals (CI).

Results: Eleven RCTs involving 811 patients were included. MSC therapy demonstrated significant reduction in VAS pain scores compared to controls (MD -4.08, 95% CI -5.56 to -2.61, p < 0.00001), with the most pronounced effects at 24-month follow-up (MD -3.31, 95% CI -5.18 to -1.44, p = 0.0005). Significant improvements were observed in IKDC scores (MD 2.88, 95% CI 0.28 to 5.47, p = 0.03), WOMAC index (MD -11.05, 95% CI -15.97 to -6.14, p < 0.0001), Lequesne index (MD -5.32, 95% CI -5.91 to -4.74, p < 0.00001), Lysholm score (MD 5.07, 95% CI 1.86 to 8.29, p = 0.002), and Tegner activity scale (MD 0.44, 95% CI 0.25 to 0.62, p < 0.00001). The therapeutic effects showed a time-dependent pattern, with maximal benefits observed at 24-month follow-up across all outcome measures.

Conclusion: Intra-articular MSC injection is an effective treatment for osteoarthritis, providing significant and durable improvements in pain relief, functional recovery, and activity levels up to 24 months post-treatment. The time-dependent nature of clinical benefits suggests a potential disease-modifying mechanism of action. MSC therapy represents a promising regenerative approach for OA management that warrants further investigation in large-scale trials.

Upon antigen recognition, naive CD4⁺ T cells are activated, exiting quiescence to undergo rapid activation, clonal expansion, and differentiation into effector functions against pathogens. T-cell activation and clonal expansion necessitate the biosynthesis of millions of new protein copies. Recent technological advancements in small RNA sequencing have revealed a highly complex and dynamic repertoire of cellular tRNAs, tRNA-m¹A58 modification, and tRNA derivatives during T-cell activation. This review outlines the basic framework of the biogenesis and biological functions of tRNAs, tRNA-m¹A58 modification, and tRNA derivatives. Importantly, we elucidate how m¹A58 modification regulates translation through multilevel mechanisms involving initiation, elongation, and termination. Furthermore, this review provides a comprehensive overview of the dynamic changes in tRNA expression repertoires and the impacts of tRNA-m¹A58 modification and tRNA derivatives on T-cell activation. This review aims to offer novel insights into the molecular mechanisms underlying T-cell activation, facilitating the development of more effective therapeutic strategies for treating T-cell-related diseases.

The incidence of pancreatic exocrine disorders, particularly pancreatic cancer, has been steadily rising. However, treatment options remain limited, with substantial interindividual variability in therapeutic efficacy. This clinical challenge has accelerated the development of advanced three-dimensional (3D) modeling systems, with patient-derived organoids and multicellular spheroids emerging as transformative tools that faithfully recapitulate tumor pathophysiology. In contrast to 2D cultures, which fail to recapitulate the three-dimensional spatial architecture and cell-cell interactions found in vivo, these models have gained prominence in pancreatic cancer research due to their unique capacity to: (1) precisely mimic the tumor microenvironment (TME), (2) preserve tumor heterogeneity, and (3) enable rapid establishment. This review systematically examines current methodologies for constructing pancreatic exocrine 3D models, their integration with bioengineering platforms for drug screening, and innovative applications in multi-omics-driven precision medicine. We further evaluate the translational potential of these systems in clinical decision-making and discuss how they may reshape therapeutic paradigms for pancreatic diseases, offering new avenues for personalized treatment strategies.

Background: Shoulder stiffness (SS) is a fibrotic disease with pain and reduced range of motion (ROM). The pathogenesis of SS remains unclear. Recent studies reveled that macrophage-myofibroblast transition (MMT) is an important mechanism underlying fibrogenesis, but whether MMT was involved in SS progression remained unknown. This study aimed to clarify the role of MMT in SS pathogenesis, and to evaluate the efficacy of MMT-targeted therapy.

Methods: Shoulder capsules from SS patients were collected, and the mouse SS model was established. Western blot and immunofluorescence were utilized to detect protein expression. Multi-omics analysis was performed in order to identify the potential pathogenic factor. Histological and biomechanical analysis was conducted for the in vivo experiments.

Results: Significant capsule fibrosis and ROM restriction were observed in both SS patients and SS mice. Upregulated MMT was detected in SS capsules. Multi-omics analysis identified periostin (POSTN) as the potential pathogenic factor. MMT was induced by POSTN in vitro. POSTN knockdown effectively attenuated MMT in mouse SS models, ameliorating capsule fibrosis and improving ROM.

Conclusion: In this study, we proved that MMT was involved in SS progression, and identified POSTN as the key regulator of MMT. POSTN knockdown effectively suppressed MMT, alleviated fibrosis, and restored ROM in vivo. This research elucidated a novel mechanism in SS pathogenesis and developed POSTN as a promising therapeutic target for SS.

Brain-Derived Extracellular vesicles (BDEVs) are emerging mediators of intra- and interorgan communication in neurodegenerative diseases (NDs) such as Alzheimer's Disease (AD) and Parkinson's Disease (PD). A growing body of evidence suggests that BDEVs play an important role in modulating intercellular communication within the central nervous system in the pathogenesis of many NDs. By transporting non-coding RNAs (e.g., miRNAs) and important pathological proteins, BDEVs also influence peripheral organs and contribute to the progression of disease in the central nervous system (CNS). This review extends the understanding of NDs beyond solely brain dysfunction and gives a novel framework for the progression of these diseases, uniquely emphasizing the currently underexplored mechanisms by which BDEV-mediated communication exacerbates or potentially initiates peripheral dysfunction or complications. It maps and clarifies the specific and potential mechanisms by which CNS-originating EV activity proliferates systemic dysfunction, presenting new opportunities and areas for therapeutic and diagnostic treatments for NDs. These findings are contextualized across multiple NDs, including Amyotrophic Lateral Sclerosis (ALS), Huntington's Disease (HD), and Multiple Sclerosis (MS), by incorporating data on dysregulated BDEV miRNAs and toxic proteins to map the pathway of BDEV-mediated disease spread.

Selecting embryos with the highest developmental potential remains a decisive step for achieving successful in vitro fertilization outcomes. Conventional evaluation methods such as morphological grading, time-lapse imaging, and preimplantation genetic testing for aneuploidy provide valuable information but are limited by subjectivity, invasiveness, and cost. These challenges have driven increasing interest in non-invasive biomarkers capable of improving the precision and safety of embryo assessment. Emerging evidence indicates that human embryos actively release microRNAs into their surrounding environment, particularly into the spent culture medium and blastocoel fluid. These extracellular microRNAs regulate pathways involved in cell cycle progression, apoptosis, differentiation, and embryo-endometrium communication. Distinct expression signatures, including miR-21-5p, miR-661, and members of the miR-17∼92 cluster, correlate with chromosomal integrity and implantation competence, suggesting their potential as complementary or alternative biomarkers to trophectoderm biopsy. Comparative analyses across digital PCR, quantitative RT-PCR, microarray, and next-generation sequencing platforms reveal both methodological advances and unresolved challenges, such as low RNA yield, contamination risk, and inconsistent normalization strategies. Embryo-derived microRNAs thus represent a promising avenue for non-invasive embryo evaluation, with future clinical translation hinging on robust multicenter validation and integration with imaging, metabolomics, and artificial intelligence-based analytics.

Introduction: Prostate cancer (PC) is one of the most prevalent malignancies in men, with rising incidence and mortality rates globally. Despite advances in therapeutic options such as androgen deprivation therapy and chemotherapy, effective cures, especially for advanced stages of the disease, remain limited. Recent research has highlighted the significant roles of alternative splicing (AS) and noncoding RNAs in tumor progression and drug resistance. This study aims to investigate the role of circIMP3, derived from the IMP3 gene, in prostate cancer development.

Methods: In this study, we employed quantitative PCR, RNA sequencing, and immunoblotting to identify and characterize circIMP3 in prostate cancer tissues and patient blood samples. Functional assays, including cell proliferation and in vivo tumorigenicity assays, were conducted to assess the biological role of circIMP3 in PC cells. RNA immunoprecipitation sequencing (RIP-seq) was used to identify alternative splicing events regulated by circIMP3. Additionally, exosome isolation and uptake assays were performed to explore the paracrine signaling function of circIMP3 within the tumor microenvironment (TME).

Results: We identified circIMP3, which is significantly upregulated in both prostate cancer tissues and peripheral blood of patients. CircIMP3 contains an internal ribosome entry site (IRES) and encodes a previously uncharacterized 288-amino-acid protein, circIMP3_288aa. Functional assays revealed that circIMP3_288aa promotes cell proliferation in vitro and accelerates tumor growth in vivo. Mechanistically, circIMP3_ 288aa regulates the alternative splicing of FBXW7, leading to impaired c-Myc ubiquitination and stabilization, which enhances oncogenic signaling. RIP-seq analysis identified over 2,000 alternative splicing events regulated by IMP3, with a notable enrichment in pathways related to ubiquitin-mediated proteolysis. Furthermore, circIMP3 is secreted into the TME via exosomes, where it is taken up by recipient cells, contributing to their proliferation.

Discussion: Our findings demonstrate that circIMP3 acts as a key regulator of both intracellular alternative splicing and extracellular paracrine signaling within the TME. The ability of circIMP3 to influence FBXW7 splicing and stabilize c-Myc provides a mechanistic basis for its role in promoting oncogenesis in prostate cancer. Clinically, high expression levels of circIMP3 correlate with poorer event-free survival in prostate cancer patients, suggesting its potential as a prognostic biomarker. Additionally, the detection of circIMP3 in peripheral blood positions it as a promising target for liquid biopsy applications in PC diagnosis and monitoring.

The development of placental organoids represents a significant breakthrough in reproductive biology, offering an advanced platform for studying human placental development and function. Unlike traditional two-dimensional (2D) cell cultures, three-dimensional (3D) organoid models, such as primary trophoblast organoids (TOs), JEG-3 organoids, and stem cell-derived organoids, provide a more robust and physiologically relevant environment. These models enable researchers to mimic the human placenta's complex architecture and cellular interactions. As a result, these advanced models promise to reveal the mechanisms underlying placental development and the associated disorders. This review compares different organoid types, highlighting their unique features and applications in studying trophoblast invasion, syncytialization, and placental barrier function. Bioinformatics approaches, particularly transcriptomic analyses, have been crucial in validating these models and identifying stage-specific markers of placental development. With challenges such as standardization issues and ethical considerations persisting, the integration of multiple organoid models, advanced technologies, and computational analyses currently provides the most comprehensive strategy for mimicking placental development across all stages in-vivo. Future directions for organoid technologies include the development of multi-organ-on-a-chip models and personalized medicine applications. This review concludes that while no single method perfectly replicates all stages of placental development, the combination of various 3D organoid models, supported by advanced technologies and computational analyses, offers the most effective approach to studying placental biology in-vivo.

Background: Prostate cancer (PCa) is frequently associated with poor prognosis, and immunotherapy has shown limited efficacy. This study aimed to identify novel necroptosis-related long non-coding RNAs (lncRNAs) that could predict patient outcomes and guide personalized treatment.

Methods: Transcriptomic data from The Cancer Genome Atlas (TCGA) were analyzed using co-expression analysis and univariate Cox regression to identify lncRNAs associated with PCa progression. A necroptosis-related lncRNA prognostic model was constructed using Least Absolute Shrinkage and Selection Operator (LASSO) and validated via Kaplan-Meier survival analysis, time-dependent receiver operating characteristic (ROC) curves, Cox regression, and calibration plots. Functional analyses included Gene set enrichment analysis (GSEA), principal component analysis (PCA), immune profiling, and half-maximal inhibitory concentration (IC50) predictions to explore therapeutic implications.

Results: We established a nine-lncRNA necroptosis-related signature with strong prognostic performance. Among these, NR2F1-AS1 was identified as a core oncogenic lncRNA, showing marked upregulation in PCa tissues and promoting proliferation, invasion, and migration in vitro. The two inferred risk groups demonstrated distinct immune characteristics: hot tumors (Cluster 2) exhibited higher infiltration of activated immune cells, increased immune checkpoint expression, and greater predicted sensitivity to immunotherapy, whereas cold tumors showed immunosuppressive infiltration patterns and lower checkpoint levels. These features allowed the model to robustly distinguish cold from hot tumor phenotypes.

Conclusion: Necroptosis-related lncRNAs, particularly NR2F1-AS1, may serve as prognostic biomarkers and inform immune-based stratification, supporting more precise personalized treatment strategies for PCa.

Obscurin is a giant protein encoded by the OBSCN gene in human myocytes, known for its roles in sarcomere organization, elasticity, stretch response, and myofibrillogenesis. Alternative splicing of OBSCN generates variants with distinct properties and localizations, including small kinase variants in mammals. Investigating obscurin-like 1 (Obsl1) and striated muscle-enriched protein (SPEG), the other members of the obscurin family in higher eukaryotes, has allowed a better understanding of obscurin family function in the sarcoplasmic reticulum, mitochondrial fragmentation, and kinase domain regulation. Obscurin's association with ankyrin isoforms in vertebrates demonstrates participation in membrane and cytoskeletal organization within muscle tissues while binding to myosin actively contributes to the formation and maintenance of the sarcomeric contractile apparatus and the M-line. The Rho-guanine nucleotide exchange factor (RhoGEF) domain of obscurin suggests a role in activating small GTPases and autoregulation. Obscurin also binds titin, indicating a dynamic function in monitoring sarcomere extension and relaying cues in muscle remodeling. Obscurin and titin can further form a tertiary complex with myomesin in vertebrates, reinforcing its importance in M-line assembly and sarcomeric organization. Beyond muscle tissue, obscurin is expressed and plays additional roles in various other organs, including skin, brain, kidney, liver, spleen, and lung. Potential tumor-suppressing properties have been revealed through OBSCN lncRNAs and epigenetic regulation. This review aims to provide a comprehensive overview of obscurin's molecular functions and interactions by discussing the effects of its differential expression and its interactions with binding partners, along with the differences and similarities between vertebrate and invertebrate obscurin.