World journal of stem cells最新文献

Mesenchymal stem cells (MSCs) are multipotent stromal cells that serve as progenitors for connective tissue and have emerged as a crucial resource in the field of tissue engineering owing to their capacity to differentiate into multiple cell lineages. MSCs-based bone regeneration strategies hold immense therapeutic potential, yet their efficacy is critically limited by inefficient osteogenic differentiation. Mounting evidence positions mitochondria as central regulators of this process, extending beyond their traditional role as cellular powerhouses. Mitochondrial regulation not only influences the induction rate of MSCs differentiation, but also determines the differentiation pathway and the ultimate fate of the resulting cells. To date, research in bone regeneration engineering has predominantly focused on the application of stem cell-based biomaterials, with limited attention given to mitochondrial development. We aim to provide a novel research perspective for targeted mitochondrial interventions in bone regeneration engineering by elucidating the mechanisms through which mitochondria regulate osteogenic differentiation of MSCs.

Bone and joint diseases, such as osteoarthritis, exhibit significant pathological complexity. Current treatment modalities possess notable limitations, driving the development of cell-free regenerative treatment strategies centered on stem cell-derived exosomes, particularly mesenchymal stem cell-derived exosomes. Despite the promise of mesenchymal stem cell-derived exosomes, several challenges impede their clinical translation. These include rapid in vivo clearance of exosomes, insufficient targeting specificity, and the difficulty of dynamically regulating the pathological microenvironment with a single delivery approach. In recent years, optimizing exosome functionality and achieving precise delivery through carrier technologies has emerged as a pivotal strategy to overcome these barriers. This review systematically evaluates the latest advancements in cutting-edge carrier technologies. These encompass biomaterial scaffolds (e.g., three-dimensional bio-printed GA/HA composite scaffolds), hydrogels, engineered and modified exosomes (e.g., cartilage affinity peptide CAP-exoASO), and nanomicrosphere co-loading systems. Research findings demonstrate that these carrier technologies enhance cartilage repair and anti-inflammatory effects via multiple mechanisms, including extending the half-life of exosomes, improving cartilage-targeting specificity, and enabling synergistic immune regulation, such as promoting M2 macrophage polarization. Preclinical studies have validated the potential of these carrier technologies. However, critical issues remain, including standardizing production processes, ensuring long-term biological safety, and evaluating cross-species efficacy. Looking ahead, multimodal delivery systems integrating gene editing, intelligent responsive materials, and personalized treatment strategies are expected to revolutionize bone and joint disease treatment by transitioning from symptom alleviation to functional reconstruction.

Background: The micro-injury of collagen fibers occurs as the tendon is stretched repeatedly between the strains of 4% and 8%, which results in the cumulative micro-damage in tendon. In prior studies, we have shown that micro-injured tendon slices with 6.4% strain promoted the chondrogenic differentiation of tendon-derived stem cells (TDSCs) through the activation of endoplasmic reticulum (ER) stress.

Aim: To investigate the potential of thymoquinone (TQ) to alleviate ER stress, and, consequently, to suppress the chondrogenic differentiation of TDSCs.

Methods: Decellularized tendon slices, subjected to micro-injury with 6.4% strain, were prepared for the culture of TDSCs. Additionally, a rat model of Achilles tendon injury via treadmill running was established. The expression levels of tenocyte and chondrocyte markers, along with ER stress-related factors, were examined in TDSCs cultured on micro-injured tendon slices, and in injured rat tendons, using reverse transcription-quantitative polymerase chain reaction, immunofluorescence staining, and western blot analysis. Furthermore, the inhibitory effects of TQ on ER stress, and the chondrogenic differentiation of TDSCs, were evaluated.

Results: In both TDSCs on micro-injured tendon slices, and injured rat tendons, tenocyte-related markers were downregulated, whereas chondrocyte-related markers were upregulated. Treatment with TQ significantly reduced the expression of ER stress markers, including glucose-regulated protein 78 (3.59 ± 0.41 vs 1.18 ± 0.23, P < 0.001), activating transcription factor 4 (2.67 ± 0.26 vs 1.16 ± 0.13, P < 0.001), CCAAT/enhancer-binding protein homologous protein (2.90 ± 0.37 vs 1.24 ± 0.35, P < 0.001), as well as phosphorylated protein kinase RNA-like ER kinase, and phosphorylated eukaryotic initiation factor 2, thereby attenuating ER stress. Furthermore, TQ diminished the chondrogenic differentiation of TDSCs, as evidenced by decreased expression of collagen II (4.80 ± 0.47 vs 1.38 ± 0.28, P < 0.001), aggrecan (2.83 ± 0.26 vs 1.44 ± 0.19, P < 0.001), and SOX9 (4.13 ± 0.46 vs 1.26 ± 0.25, P < 0.001), effects comparable to those observed with 4-phenylbutyric acid.

Conclusion: These findings suggested that TQ inhibited the protein kinase RNA-like ER kinase/eukaryotic initiation factor 2/activating transcription factor 4/CCAAT/enhancer-binding protein homologous protein signaling pathway to alleviate ER stress, thereby reducing the chondrogenic differentiation of TDSCs, both in vitro and in vivo.

GrpE-like 1 (GRPEL1)-carrying exosomes derived from synovial mesenchymal stem cells (SMSC) prevent mitochondrial dysfunction associated with osteoarthritis (OA) by activating PINK1-mediated mitophagy, restoring chondrocyte function, and preserving the extracellular matrix both in vitro and in vivo. Bioinformatics analysis of human OA datasets identified GRPEL1 as a mitophagy-related gene that is downregulated in OA. Exosomes enriched with GRPEL1 derived from SMSCs enhanced mitochondrial membrane potential and ATP production, reduced lipid peroxidation and reactive oxygen species, increased mitophagy markers (PINK1, Parkin, LC3-II/I), decreased p62 levels, and alleviated cartilage degeneration in a rat destabilization model. A causal role for mitophagy is supported by co-immunoprecipitation experiments confirming a GRPEL1-PINK1 interaction, and by PINK1 knockdown, which diminishes the protective effects of GRPEL1. These findings suggest that exosomes enriched with GRPEL1 derived from SMSCs represents a promising disease-modifying approach for OA by targeting mitochondrial quality control.

Type 2 diabetes mellitus, particularly when accompanied by obesity, has become a major global public health burden. Visceral adipose tissue accumulation contributes to insulin resistance, lipotoxicity, and chronic inflammation, thereby accelerating metabolic deterioration. Although pharmacological agents such as pioglitazone and metformin are effective in modulating fat distribution and improving metabolic parameters, their roles in adipose tissue remodeling remain insufficiently elucidated. Recent advances in regenerative medicine have highlighted the therapeutic potential of adipose-derived stem cells, owing to their differentiation capacity, anti-inflammatory secretory profile, and involvement in metabolic homeostasis. This review summarized current pharmacological and stem cell-based strategies targeting adipose tissue dysfunction in patients with obesity and type 2 diabetes mellitus with a particular focus on the mechanistic roles of adipokines, mitochondrial dysfunction, and extracellular matrix remodeling in visceral adipose tissue. It further discussed the potential synergistic benefits of adipose-derived stem cell-based combination interventions. Finally, the review envisioned future directions for integrating molecularly targeted drugs with cell therapies in the personalized management of metabolic disorders.

This article comments on the study by Fang, which demonstrates that reduced nuclear factor erythroid-derived 2 (NRF2) activity promotes endoplasmic reticulum stress and senescence in adipose-derived mesenchymal stem cells from hypertrophic obese mice, primarily through downregulation of mitofusin-2 (MFN2). Robust methodologies, including knockdown/rescue experiments, chromatin immunoprecipitation quantitative polymerase chain reaction, co-immunoprecipitation, and transplantation assays, substantiate that NRF2 or MFN2 disruption impairs the therapeutic potential of these cells in insulin resistance. However, the proposed MFN2-binding immunoglobulin protein interaction remains indirectly supported and requires biochemical validation (e.g., glutathione S-transferase pull-down/Forster resonance energy transfer/cross-linking mass spectrometry). Moreover, NRF2 may influence endoplasmic reticulum stress and senescence through additional unexplored targets. Future studies should clarify the structural and functional nature of the MFN2-binding immunoglobulin protein relationship and its implications for mitochondrial dynamics, endoplasmic reticulum-mitochondria tethering, and calcium signaling.

Background: Mesenchymal stem cells (MSCs), as a living bio-drug, are being considered as a potential treatment for coronavirus disease 2019 (COVID-19)-induced acute respiratory distress syndrome (ARDS) due to their immunomodulatory and reparative properties.

Aim: To synthesize the existing evidence on MSCs and their derivative exosomes for treating COVID-19-induced ARDS, with a focus on the key outcomes of safety and efficacy.

Methods: Four databases were systematically searched for randomized controlled trials assessing MSCs and their derived exosomes for COVID-19-induced ARDS treatment. Their safety and efficacy were evaluated based on the duration of mechanical ventilation, hospital and intensive care unit stay, 6-minute walk distance, mortality rates, and adverse events. Weighted mean differences and odds ratios with 95% confidence intervals (CIs) were calculated to estimate treatment outcomes: A network meta-analysis (NMA) evaluated mortality, adverse events, and the number of ventilation-free days.

Results: Sixteen randomized controlled trials involving 1027 ARDS patients were included, with 574 receiving MSCs or MSC-derived exosomes. MSC-based therapy did not significantly improve mechanical ventilation duration, ventilation-free days, hospital or intensive care unit stay, or 6-minute walk distance. Sensitivity analysis revealed a significant reduction in mechanical ventilation duration when excluding an outlier (weighted mean difference: -4.84 days; 95%CI: -8.21 to -1.47; I ² = 20%). In contrast, no significant differences were observed in the other outcomes. Mortality and adverse events were comparable between the groups (odds ratio for mortality: 0.77; 95%CI: 0.56-1.06). An NMA of ventilation-free days, mortality, and adverse events revealed no significant difference among MSCs, exosomes, and controls. Exosomes ranked highest in terms of probability of benefit, although without statistical significance.

Conclusion: MSC and exosome-based therapies were found to be safe and associated with a reduced duration of mechanical ventilation in patients with ARDS. NMA showed that exosome-based therapy matched the benefits of its parent cells, but with practical and logistical advantages.

Background: Osteoarthritis (OA) remains a challenging degenerative joint disease with limited therapeutic interventions.

Aim: To investigate the potential of synovial mesenchymal stem cell (SMSC)-derived exosomes (SMSCs-Exos) delivering GrpE-like 1 (GRPEL1) in promoting cartilage repair through phosphatase and tensin homolog-induced putative kinase 1 (PINK1)-mediated mitophagy activation.

Methods: A comprehensive research approach was employed, including bioinformatics analysis of gene expression datasets (GSE169077 and GSE114007), in vitro experiments with CHON-001 chondrocytes, and in vivo rat knee OA models. Experimental techniques encompassed gene expression profiling, immunofluorescence staining, western blot analysis, co-immunoprecipitation, cell proliferation and migration assays, and histological examinations. Exosomes were genetically modified to overexpress or knockdown GRPEL1, and their effects on cellular function and mitochondrial dynamics were systematically evaluated.

Results: Bioinformatics analysis revealed GRPEL1 as a critical mitophagy-related gene with significantly altered expression in OA. In vitro studies demonstrated that GRPEL1-loaded SMSCs-Exos effectively counteracted interleukin-1 beta-induced cellular damage by enhancing chondrocyte proliferation and migration, preserving extracellular matrix integrity. Mechanistic investigations confirmed direct interaction between GRPEL1 and PINK1, leading to enhanced mitophagy activation. In vivo rat models substantiated these findings, showing significantly reduced cartilage damage, restored proteoglycan content, and improved joint structure in groups receiving GRPEL1-overexpressing exosomes. Key molecular changes included decreased reactive oxygen species, improved mitochondrial membrane potential, and increased mitophagy markers.

Conclusion: This study provides compelling evidence that SMSCs-Exos delivering GRPEL1 can effectively activate PINK1-mediated mitophagy, offering a promising therapeutic strategy for cartilage repair in OA. The research unveils a novel molecular mechanism for targeting mitochondrial dysfunction and presents a potential disease-modifying approach beyond current symptomatic treatments.

The cohort study by Li et al provides timely and clinically relevant evidence on the use of recombinant human thrombopoietin (rhTPO) in pediatric allogeneic hematopoietic stem cell transplantation. The authors report enhanced platelet engraftment and a favorable safety profile, particularly in younger children aged 0-9 years. This age-dependent difference not only highlights the physiological responsiveness of early hematopoietic environments to rhTPO but also raises important questions about tailoring supportive therapies across pediatric age groups. While the findings are promising, the lack of a control group and single-center limitations warrant further multicenter, long-term investigations. Nevertheless, the study lays a compelling foundation for integrating rhTPO more broadly into pediatric transplant protocols and for advancing individualized post-transplant care.

Microplastics (MPs), defined as plastic particles with diameters less than 5 mm, have become significant global environmental contaminants. MPs accumulate in human tissues and organs, raising significant concerns about their potential biological toxicity. Evidence indicates that MPs and associated toxins disrupt stem cell self-renewal, proliferation, and differentiation processes essential for tissue regeneration and systemic homeostasis, yet research on MP-induced stem cell damage remains limited. To identify relevant and recent studies, we searched the PubMed database using title and abstract fields. This review synthesizes current evidence across organ systems, including nervous, hematopoietic, skeletal, and urinary systems, to systematically categorize phenotypic disruptions and underlying mechanisms in stem cells. We further evaluate the utility of stem-cell-derived organoids in modeling organ-specific MP toxicity. By consolidating fragmented findings, this work provides a critical framework for assessing MP risks to tissue regeneration and informs strategies for regenerative medicine and public health protection.