Frontiers in Cell and Developmental Biology最新文献

The management of chronic wounds remains challenging due to their complex pathophysiology, poor response to conventional therapies, and significant impact on patients' quality of life. mesenchymal stem cells (MSCs) have garnered attention as a potential treatment due to their regenerative and immunomodulatory properties. This review summarizes preclinical and clinical advancements in MSC-based therapies for chronic wound healing. MSCs promote tissue regeneration through various mechanisms, including differentiation into skin cell lineages, modulation of inflammation, angiogenesis, and paracrine release of bioactive factors. Current research focuses on identifying viable MSC sources, optimizing delivery methods, and understanding their mechanisms for clinical use. Despite progress, challenges remain, including inconsistent results, poor MSC survival in the wound microenvironment, and variability in regenerative capacity across MSC sources. Future research should focus on developing standardized guidelines for MSC preparation and conducting long-term randomized trials to assess safety, efficacy, and potential risks. In conclusion, this review highlights current evidence and identifies key challenges for the clinical application of MSCs in chronic wound healing.

Introduction: Cancer cells display a high degree of heterogeneity in their responses to mitotic arrest, from apoptosis during mitosis to surviving mitotic failure and continuing to progress through the cell cycle. Thus, understanding the basis for this variation may prove valuable for developing more effective chemotherapeutic strategies.

Methods: A combination of biochemical and long-term live cell imaging approaches were applied to determine whether inhibition of Phosphoinositide 3-kinase (PI3K) signaling affected apoptosis in cancer cells arrested in prometaphase with a Kinesin Spindle Protein (KSP) inhibitor.

Results: Dual inhibition of KSP and PI3K signaling induced apoptosis more effectively than mitotic arrest or PI3K pathway inhibition alone. Live cell imaging with probes for mitotic progression and apoptosis revealed that HeLa cells that died during mitotic slippage underwent apoptosis during prometaphase arrest, suggesting that PI3K inhibition dramatically shifted the dynamics of cell death. Similar potentiation of mitotic cell death could be detected in SiHa cells, whereas other cancer or non-transformed cell lines were not sensitized by PI3K inhibition. Expression of constitutively active Rap1, which modulates both cell adhesion and PI3K activity, significantly increased the duration of mitotic arrest in a PI3K-dependent manner. Moreover, activated Rap1 significantly increased the fraction of cells that slipped completely back into interphase prior to apoptotic cell death.

Conclusions: These results shed insights into possible mechanisms by which cells may evade cell death during mitotic delay and suggest a strategy to optimize antimitotic interventions.

Lower back pain (LBP) caused by intervertebral disc (IVD) degeneration is a major global health burden, with significant socioeconomic costs. This review examines proteolytic enzyme-based models for inducing IVD degeneration, focusing on their advantages over mechanical and puncture methods, which often fail to replicate the chronic, multifactorial nature of human degeneration. Enzymatic models, such as chemonucleolysis using chondroitinase ABC (ChABC), chymopapain, collagenase, papain, and trypsin, selectively degrade extracellular matrix components like aggrecan and collagen, mimicking the biochemical and structural changes seen in human IVD degeneration. These models offer controlled, reproducible, and physiologically relevant platforms for studying disease progression and evaluating regenerative therapies. Key findings include the dose- and time-dependent effects of enzymes on disc height loss, biomechanical properties, and matrix composition, as well as their ability to induce mild to moderate degeneration without acute trauma. Comparative studies highlight ChABC's suitability for early-stage degeneration, while chymopapain and papain produce more severe changes. Enzyme models also provide insights into cellular responses, such as cytokine upregulation and matrix remodeling, which are critical for developing targeted treatments. By enabling precise modulation of degenerative severity, these models hold promise for advancing preclinical research and optimizing regenerative strategies for IVD repair. Looking forward, integrating behavioral and molecular pain outcomes into enzyme-based systems may further enhance their translational value, allowing future models to capture both structural and symptomatic dimensions of disc disease.

Introduction: Chimeric antigen receptor macrophages (CAR-Ms) represent a novel approach in cellular immunotherapy. Human pluripotent stem cells (hPSCs) provide an unlimited and renewable cell source, enabling scalable and standardized production of CAR-Ms with consistent quality.

Methods: In this study, we established a robust differentiation protocol to generate CAR-Ms from hPSCs. To evaluate HER2-directed hPSC-derived CAR-M functionality, we first profiled HER2 expression across multiple tumor cell lines and identified SKOV3 as the optimal target due to its high HER2 level. CAR constructs incorporating intracellular domains from CD3ɛ, FCGR1A, FCGR2A, FCGR2B, and FCGR3A were introduced into hPSCs via lentiviral transduction.

Results: Importantly, CAR expression did not impair hPSCs differentiation into macrophages. Functional assays revealed that all CAR-Ms exerted cytotoxic effects on HER2-positive SKOV3 cells, with FCGR2A-based CAR-Ms demonstrating the strongest activity. Furthermore, polarization of CAR-Ms into a proinflammatory state significantly enhanced tumor-killing efficacy, particularly in FCGR2A CAR-Ms.

Discussion: These findings highlight the potential of FCGR2A as an optimal signaling domain for CAR-M design and underscore the therapeutic promise of proinflammatory polarized CAR-Ms in solid tumor immunotherapy.

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.