Transposable elements (TEs), which are under tight epigenetic control, have been co-opted as cis-regulatory elements to regulate gene expression during development and cancer. Among them, long interspersed element 1 (LINE-1) retrotransposons are the most abundant and exhibit high activity in embryonic stem cells. However, the precise role of LINE-1 in breast cancer stem cells (BCSCs) remains poorly understood. Here, using RNA sequencing, an enhancer dual-luciferase reporter assay, and a nuclease-dead Cas9 (dCas9)-based CRISPR activation (CRISPRa) assay, we show that the LINE-1 retrotransposon L1Md_T within Sema3c (Sema3c_L1Md_T) is derepressed and functions as a cis-regulatory enhancer that drives SEMA3C expression to sustain mouse BCSC survival. In mouse BCSCs, Sema3c_L1Md_T results in the formation of more phase-separated nuclear condensates with the transcriptional coactivator BRD4 under conditions of increased chromatin accessibility. BRD4 puncta coincide with regions marked by histone H3 lysine 27 acetylation (H3K27ac), enhancing the transcription of SEMA3C. Aberrant SEMA3C expression contributes to mouse BCSC survival and self-renewal via its receptor NRP1 and the coreceptors PlexinA2/PlexinD1. Importantly, we also demonstrate that this regulatory mechanism is conserved in human breast cancer, where SEMA3C is highly expressed in human BCSCs. A human LINE-1 element (SEMA3C_L1ME4a) exhibits enhancer activity and colocalizes with BRD4 condensates in human BCSCs. These findings confirm that the LINE1-BRD4-SEMA3C regulatory axis is present in both mouse and human BCSCs, underscoring its translational relevance. Notably, pharmacological degradation of BRD4 using the proteolysis-targeting chimaera (PROTAC) MZ1 reduces SEMA3C levels and decreases BCSC viability both in vitro and in vivo. Our study reveals an oncogenic role for a LINE-1-derived enhancer in regulating SEMA3C transcription and sustaining BCSC properties, highlighting BRD4 as a therapeutic vulnerability in BCSC-driven breast cancer progression.

Depletion of TRF2 from chromosome ends causes telomeric fusions and genome instability in mammals, but in mouse neural stem cells (mNSCs), Trf2's role is non-telomeric. Although essential for mNSC proliferation and survival, Trf2 does not protect telomeres, aligning with findings that Trf2 is dispensable for telomere protection in pluripotent stem cells. In Trf2-deficient adult mNSCs (Trf2fl/fl; Nestin-Cre), proliferation decreased and neuronal differentiation was impaired, yet no telomere dysregulation or DNA damage response was observed. Similarly, TRF2 depletion in SH-SY5Y cells induced differentiation without telomere dysfunction. Mechanistically, non-telomeric TRF2 directly binds to the promoters of key genes that regulate differentiation, recruiting the polycomb repressor complex (PRC2) for H3K27 trimethylation, repressing differentiation genes to maintain NSC identity. G-quadruplex (G4) motifs are crucial for TRF2 binding; disrupting this interaction via G4-binding ligands or the G4-specific helicase DHX36 induces differentiation genes, promoting neurogenesis. These findings highlight TRF2's non-telomeric role in NSC survival, offering insights into neurogenesis and aging-related neurodegeneration.

Although stem cell therapies are now used in medicine, they have not yet been approved in dentistry. The authors compared periodontists' and oral maxillofacial surgeons' (OMSs) knowledge, interests, and thoughts about the adoption of stem cell-based therapy for use in oral and craniofacial reconstructive procedures.

Uveal melanoma (UM), the most prevalent primary intraocular cancer in adults, is defined by salient histopathological diversity. Spindle and epithelioid cells constitute its two dominant pathological lineages, yet the latter foreshadows aggressive behavior and shortened survival. This study aimed to explore the molecular and metabolic underpinnings of UM pathology using regionally resolved proteomics.

Critical-sized bone defects caused by trauma, tumor resection, injury, and/or surgical intervention are posing significant clinical challenges. Bone tissue regeneration is crucial for restoring critical-sized bone defects. Central to the bone regenerative capability is the dynamic interplay between bone cells, particularly osteocytes, which are the most abundant and long-lived bone cells, functioning as key mechanosensors in bone. Osteocytes detect mechanical stimuli, for example, fluid shear stress, compressive or tensile strain, and hydrostatic pressure, and convert these into biochemical signals through mechanotransduction. The biochemical signals (eg, calcium ions, Wnt, etc.) regulate osteoblast and osteoclast-mediated remodeling. Osteocytes communicate with osteoblasts and osteoclasts via paracrine factors, including nitric oxide, prostaglandins, and sclerostin. Moreover, estrogen deficiency is known to alter osteocyte mechanosensitivity, impair osteocyte signaling, and dysregulate bone remodeling. Understanding how mechanical and hormonal factors affect osteocyte signaling is essential for developing effective therapeutic interventions. This concise review explores the role of osteocyte mechanosensing and mechanotransduction in bone tissue regeneration to improve bone healing, especially in critical-sized bone defects. The cellular and molecular mechanisms underlying bone regeneration and remodeling are discussed, including the role of stem cells in bone regeneration, that is, osteogenic differentiation potential and secretion of bioactive factors that promote new bone formation and vascularization. Finally, we explore the translational and clinical implications of osteocyte mechanobiology, discussing current challenges and potential advancements in bone tissue engineering and regenerative medicine. By integrating fundamental mechanobiological principles with clinical strategies, this concise review highlights the clinical potential of modulating osteocyte behavior for improved bone regeneration.

Dietary restriction (DR) is a robust lifespan-extending intervention across species. While budding yeast is a fundamental model for DR, results from glucose restriction (GR) often show inconsistencies. This may stem from auxotrophic markers in engineered strains, which can induce abnormal cellular states under starvation. We hypothesized that GR extends chronological lifespan (CLS) primarily by avoiding auxotrophic starvation, thereby allowing cells to better adapt to nutrient depletion. Using non-dividing survival assays for precise nutritional control, we observed that yeast survive significantly longer under carbon starvation than under auxotrophic starvation. The extent of CLS extension was diminished when auxotrophic starvation was absent. Yeast cells under auxotrophic starvation showed decreased resistance to H2O2 and increased mutation rate-phenotypes that suggest a failure to enter a robust, quiescent-like state. These findings suggest that auxotrophic starvation may bias not only CLS studies but also broader yeast studies. By reconsidering previous studies with attention to auxotrophic starvation, more meaningful conclusions could emerge. Since auxotrophic nutrients in yeast are analogous to essential amino acids in higher organisms, our findings have broader implications for understanding DR in various species.

The use of umbilical cord blood (UCB) as a stem cell source in haematopoietic stem cell transplant (HSCT) has greatly declined in recent years. It has largely been replaced by mismatched unrelated and family donors, facilitated by advances in transplant technologies, including post-transplant cyclophosphamide to prevent graft-versus-host disease (GVHD). UCB remains a distinctive source of haematopoietic stem cells (HSCs) with unique immunologic and practical advantages, including for those with malignant and non-malignant diseases. Compared to other cell sources, UCB transplantation (UCBT) offers comparable survival with reduced chronic GVHD (cGVHD) and with a potent graft-versus-leukaemia (GVL) effect. These outcomes likely reflect the biology of cord-derived lymphocytes-particularly naïve, adaptable CD8+ T-cells capable of rapid differentiation and tumour-directed cytotoxicity without sustained alloreactivity. UCB permits greater human leukocyte antigen (HLA) mismatch tolerance, especially when transplant is performed T-cell replete and can be accessed immediately, reducing time to transplant for high-risk leukaemia. In addition, recent advances in ex vivo expansion technologies have overcome historical limitations of low cell dose and delayed engraftment, expanding UCB's applicability to older paediatric and adult recipients. This review discusses the evidence of using UCB as a preferred stem cell source in patients with relapsed/refractory haematological malignancies and how we may interrogate the properties of UCB to improve outcomes in these high-risk cohorts.

Macrophages exhibit extensive tumor infiltration capacity across diverse solid malignancies, establishing macrophage-targeted immunotherapies as an emerging frontier in oncology. Genetic engineering of macrophages using chimeric antigen receptor (CAR) technology - enabling recognition and phagocytosis of neoplastic cells - is emerging as a potential therapeutic strategy against solid tumors. Human induced pluripotent stem cells (iPSCs) provide a renewable platform for the efficient differentiation of functionally competent macrophages. In this study, we engineered human iPSC-derived CAR macrophages (iCAR-M) targeting interleukin-13 receptor subunit alpha 2 (IL-13Rα2). Pan-tumor transcriptomic and immunohistochemical analyses revealed that IL-13Rα2, a tumor-associated antigen, was overexpressed in human glioblastoma (GBM), uterine carcinosarcoma (UCS), and melanoma specimens. In vitro phagocytosis assays revealed target-specific clearance of IL-13Rα2-positive tumor cells by iCAR-M. Intracranial administration of iCAR-M potently suppressed tumor growth, enhanced intratumoral cytotoxic T-cell infiltration, and prolonged the survival of humanized, immunocompetent mice bearing GBM xenografts. The administered iCAR-M maintained phagocytic capacity in vivo and acquired an M1-like pro-inflammatory phenotype. Comprehensive safety assessment revealed no detectable evidence of systemic toxicity or treatment-related neurotoxicity. Collectively, these results demonstrate the potent efficacy and favorable safety profile of iPSC-derived, IL-13Rα2-targeted CAR macrophages, supporting their therapeutic potential against solid tumors. © 2026 The Pathological Society of Great Britain and Ireland.

Endometriosis is a benign gynaecological disorder characterised by the presence of endometrial-like tissue outside the uterus. Proliferation of endometrial tissue and neoangiogenesis are essential factors in the development of endometriosis. Vascular endothelial growth factor (VEGF) and insulin-like growth factors (IGF1, IGF2) can be effective in neoangiogenesis and cell proliferation. Imprinted long non-coding RNA (lncRNA) H19 is involved in endometriosis pathogenesis through the regulation of cellular proliferation and differentiation. Curcumin has antiangiogenic, anti-proliferative, and anti-invasive properties for various diseases, and it is hypothesised that it may have therapeutic effects on endometriosis. This study aimed to evaluate the effects of curcumin on the expression of VEGF, IGF1, IGF2, and H19 lncRNA, as well as on cell migration and proliferation in endometrial stromal cells isolated from women with endometriosis.

This review highlights recent advances in ovarian organoid research. Ovarian organoids are three-dimensional (3D) structures derived from primary ovarian tissues, cancer cells, or stem cells that replicate key architectural and functional features of native ovarian tissue. Their formation requires both germ cells, such as oocytes and primordial germ cells, and somatic cells, including stromal, thecal, follicular, and epithelial cells. Ovarian organoids are typically characterized through histological, molecular, and functional analyses to confirm their structural and transcriptional resemblance to the native ovary. These organoids contain a heterogeneous population of cell types, reflecting the cellular diversity of ovarian tissue, and exhibit gene expression profiles closely aligned with those of primary ovarian tissues. Organoids derived from both normal and malignant sources hold great potential for a wide range of applications, including basic ovarian biology, cancer research and therapeutics, fertility studies, drug screening, disease and cancer modeling, endocrine function studies, personalized medicine, and pathogen interaction analysis. Despite existing technical and biological challenges, ongoing research and innovations continue to expand the potential of ovarian organoids in reproductive biology and disease management.

Adult neurogenesis, the generation of new neurons in the adult brain, acts as a fundamental driver of neural plasticity within specialized microenvironments. The integrity of the hippocampal subgranular zone, essential for pattern separation and mood regulation, relies on a functional syncytium formed by the vasculature, glial cells, and neural stem cells (NSCs). This review delineates the architecture of this system, detailing how the vascular pillar provides angiocrine support via vascular endothelial growth factor (VEGF) and brain-derived neurotrophic factor (BDNF), while the glial pillar-comprising astrocytes and microglia-orchestrates metabolic homeostasis and immune surveillance. The dynamic regulation of this local ecosystem by systemic factors, including physical exercise and the gut-brain axis, is also explored. Furthermore, the breakdown of this alliance is examined as a pathological hub in aging, Alzheimer's disease (AD), and chronic stress. Crucially, the text addresses the significant translational gap between rodent models and human physiology. The ongoing controversy regarding the persistence of adult human neurogenesis is critically evaluated, attributing conflicting data to methodological variables such as postmortem interval (PMI) and fixation kinetics. Additionally, the risks of maladaptive plasticity, where aberrant neurogenesis contributes to conditions like epilepsy, are discussed. Finally, future directions involving high-resolution omics and imaging are highlighted, emphasizing that therapeutic strategies must navigate the complex biological risks of neural repair.

To explore the dynamic changes in excitability and viability of induced pluripotent stem cells (iPSC)-derived motor neurons from sporadic amyotrophic lateral sclerosis (ALS) and compare them with SOD1-related ALS patients and healthy control.

Adult hippocampal neurogenesis (AHN) supports learning, memory, and emotional regulation, and is regulated by intrinsic and extrinsic factors. Dopamine influences neurogenesis in animal models, but its direct effects on human hippocampal progenitors and receptor-specific mechanisms remain unclear. This study examined the dose-dependent effects of dopamine on proliferation, differentiation, and survival of human hippocampal progenitor cells (HPC0A07/03) in vitro, and assessed dopamine D4 receptor (DRD4) involvement. Cells were treated with dopamine (1-150 µM) under proliferation and differentiation conditions, with DRD4 modulated via selective agonist, antagonist, or combined treatment. Proliferation (Ki67), stemness (SOX2, Nestin), neuronal differentiation (DCX, MAP2), apoptosis (CC3), total cell counts, and morphology (cytoplasmic area) were assessed using immunocytochemistry, alongside targeted gene expression analysis of cellular stress- and neurogenesis-related pathways. Treatment with supraphysiological dopamine concentration (150 µM) significantly reduced cell counts during differentiation and decreased SOX2 expression during proliferation, suggesting impaired survival and reduced stemness. Complementary transcriptional changes supported a stress-associated cellular response at high dopamine concentrations. Elevated dopamine (150 µM) also increased cytoplasmic area in immature DCX+ neurons during the differentiation phase, suggesting altered morphological maturation. Moderate dopamine concentration (30 µM) showed a trend toward increased proliferation and higher cell counts. No significant changes occurred for other markers or following DRD4 modulation. These findings indicate that dopamine's effects on human hippocampal progenitors are dose-dependent: supraphysiological levels may compromise survival and progenitor identity, potentially via stress-related mechanisms, whereas moderate levels may support neurogenic processes. Understanding this dose-dependent balance has implications for neurological and psychiatric disorders involving dopaminergic dysregulation.

CRISPR-Cas9 (clustered regularly interspaced short palindromic repeats and CRISPR-associated protein 9)-based gene editing represents a promising frontier for treating monogenic hematologic disorders. Several preclinical studies have demonstrated the transplantation efficiency of CRISPR-Cas9-mediated gene editing in hematopoietic stem and progenitor cells (HSPCs) using various animal models. Nonetheless, these studies have employed diverse gene-editing strategies, utilizing HSPCs from different origins and transplanting them into distinct mouse strains. The present study aimed to determine the optimum conditions for efficient engraftment of genetically modified HSPCs across various organs, thereby facilitating the translation of preclinical research into clinical applications.

The aim of the study was to compare post-transplant cyclophosphamide (PTCY)-based regimens with historical regimens using calcineurin inhibitor and methotrexate (CNI-MTX) for allogeneic hematopoietic stem-cell transplant (HCT) in nonmalignant hematologic disorders.

Mitochondrial health is increasingly recognized as a critical determinant of immune competence during the perioperative period. Surgical interventions impose unique metabolic and inflammatory stresses-such as ischemia-reperfusion injury, anesthetic exposure, and systemic inflammatory responses-that impair immune cell bioenergetics and redox balance. Dysfunctional mitochondria in neutrophils, macrophages, and T lymphocytes alter cytokine production, phagocytic activity, and antigen presentation, tipping the balance toward excessive inflammation or postoperative immunosuppression, thereby exacerbating organ injury. This review integrates current knowledge of the mechanisms linking perioperative mitochondrial dysfunction to immune dysregulation, and systematically evaluates emerging therapeutic strategies, including mitochondrial-targeted antioxidants, permeability transition pore inhibitors, metabolic reprogramming agents, mitochondrial transplantation, and gene-based interventions. By bridging experimental evidence with translational and early clinical studies in cardiac, neurological, hepatic, and renal surgeries, we argue that precise modulation of immune cell mitochondrial function represents a promising and underexplored frontier for comprehensive perioperative organ protection.

Spinal cord injury (SCI) is a highly disabling disorder of the central nervous system for which no curative therapy is currently available. In recent years, extracellular vesicles - particularly exosomes - have been investigated as cell-free therapeutic approaches in experimental models, owing to their low immunogenicity, favorable biocompatibility and capacity to traverse the blood-spinal cord barrier under specific conditions or delivery routes. This Review summarizes the therapeutic activities and mechanisms of exosomes from diverse sources - including mesenchymal stem cells, immune cells and neural cells - in SCI repair. Reported mechanisms include modulation of the inflammatory microenvironment; inhibition of apoptosis and pyroptosis; mitigation of ferroptosis; promotion of angiogenesis and axonal regeneration; and restriction of glial scar formation. We also discuss advances aimed at enhancing exosome efficacy through cell preconditioning, engineering strategies and integration with biomaterials. Although exosome-based approaches are promising, challenges remain in standardization, targeted delivery and long-term safety. Future work should elucidate the underlying mechanisms and advance clinical translation to robustly evaluate the therapeutic potential of exosomes for SCI repair.

Mesenchymal stromal/stem cell-derived extracellular vesicles (MSC-EVs) have emerged as promising acellular therapeutics in regenerative medicine, offering a safer and more controllable alternative to whole-cell therapies. Their therapeutic efficacy, however, is highly dependent on their molecular cargo, which reflects the physiological state and environmental conditions of the parent MSCs. Priming of mesenchymal stromal/stem cells (MSCs) with defined stimuli such as hypoxia, inflammatory cytokines, 3D culture systems, biomaterials, or pharmacological agents has been increasingly employed to enhance extracellular vesicle (EV) bioactivity. These strategies modulate EV content, enriching vesicles with regenerative, immunomodulatory, angiogenic, and antioxidant factors. For instance, hypoxic priming activates hypoxia-inducible factor-1α-driven gene expression, promoting the packaging of angiogenic and anti-inflammatory molecules, while cytokine-based priming upregulates immunosuppressive proteins and regulatory microRNAs. Similarly, 3D culture mimics aspects of the native tissue microenvironment, augmenting the secretion of EVs with enhanced reparative potential. Emerging combination-based approaches synergize these effects, generating EVs with superior therapeutic profiles. Despite encouraging preclinical data, translation to clinical application is challenged by variability in MSC sources, priming conditions, and EV isolation methods. Standardization of protocols, validated potency assays, and regulatory harmonization are critical for clinical advancement. This mini-review summarizes current priming strategies, the underlying mechanisms influencing EV cargo, and their functional implications in disease models, while highlighting key barriers and future directions for the clinical translation of primed MSC-EV therapies.

Aim: Extracellular vesicles (EVs) released by mesenchymal stem cells (MSCs), known as MSC-EVs, have gained attention as potential treatments owing to their immunomodulatory functions. Despite growing clinical interest, donor-to-donor inconsistencies remain key challenges for standardizing MSC-EV production under good manufacturing practice (GMP) conditions. This work aimed to systematically compare the molecular and functional consistency of EVs derived from three independent human adipose tissue-MSC donors. Methods: GMP-grade EVs were initially isolated using tangential flow filtration on a large scale and then characterized by multiple biophysical analyses. To characterize the protein composition of EVs across batches, quantitative proteomic analysis was performed using tandem mass tags and mass spectrometry. For functional validation, an in vitro macrophage inflammation assay was conducted by treating natural lipopolysaccharide-stimulated cells with EVs, and cytokine levels were measured using enzyme-linked immunosorbent assays (ELISA). Results: Quantitative proteomic profiling identified 2,615 proteins, of which 84%-94% were not significantly changed across batches, highlighting a robust core proteome. Notably, 361 membrane-associated proteins were consistently conserved, including transporters, adhesion molecules, and signaling receptors, implicating these components in EV-mediated intercellular communication and immunomodulation. Functional analysis using an in vitro macrophage inflammation model demonstrated that all EV batches reproducibly suppressed pro-inflammatory cytokine production in a dose-dependent manner, with no significant inter-batch differences. Conclusion: Collectively, these findings indicate that MSC-EVs maintain both molecular and functional stability across different donors, and that a conserved proteomic signature underlies their reproducible anti-inflammatory activity. This study provides a foundation for establishing standardized quality criteria and advancing MSC-EVs toward clinical therapeutic applications.

A recent study on Cell Reports Medicine by Wang et al. introduces a hybrid exosome platform - selenized neural stem cell-derived exosomes (SeNExo) - that couples the biological functionality of neural stem cell exosomes with the antioxidant power of ultrasmall nanoselenium. SeNExo crosses the blood-brain barrier via apolipoprotein E (APOE)-lipoprotein receptor-associated protein-1 (LRP1) interaction, scavenges reactive oxygen species, and restores glial-neuron homeostasis. It demonstrates potent therapeutic efficacy in both traumatic brain injury and spinal cord injury mouse models. This work highlights a promising direction for engineering multifunctional, cell-free nanotherapeutics for central nervous system repair.