Zinc is a component of the antioxidant defense system. Its functions protecting biological systems from oxidation are exerted at multiple levels including competing with redox active metals for binding sites, dynamically interacting with thiol groups and inducing metallothionein (MT) expression, regulating oxidant production, and increasing antioxidant defenses in part via NRF2 modulation. Zinc also directly and indirectly modulates redox regulated signaling cascades. Zinc deficits can affect not only the capacity of cells to defend against oxidative challenges but also alter redox signaling that modulate key cellular processes. Zinc is essential at different stages of development given its capacity to regulate key participating processes, e.g. cell proliferation, differentiation and survival. In the developing brain, the adverse consequences of a decrease in zinc availability depend on the severity and the timing of the deficiency. While gestational severe zinc deficiency causes teratogenesis in the brain and several other organs, mild zinc deficiency has significant deleterious consequences on the neural stem cell pool, neurogenesis, oligodendrogenesis, and astrogliogenesis in the offspring. Alterations in neuron, oligodendrocyte and astrocyte number, neuronal specification and myelination associated with zinc deficits in early development persist into adulthood, affecting behavior and motor performance. This review will focus on the role of zinc on brain development and on the interconnection between zinc and the redox tone in shaping different windows of neurodevelopment.

Bone marrow organoids (BMOs) are three-dimensional cell culture models that recapitulate key structural and functional features of the bone marrow (BM) niche. BMOs offer important advantages in hematopoietic research by modeling key aspects of human hematopoiesis compared to classical in vitro two- and three-dimensional cellular models including bioreactors, BM-on-a-chip platforms, 2D models or BM ossicles by better recreating the three-dimensional architecture, cellular heterogeneity, and spatial organization of the BM microenvironment. They offer a scalable and cost-effective alternative to animal models and reduce the need for animal experiments. Induced pluripotent stem cell (iPSC)-derived BMOs can be generated from a patient's own cells, enabling personalized disease modeling and drug testing and are highly amenable to gene editing technologies allowing precise modifications to study gene function or model diseases. Recent landmark studies from Christoph Klein and Abdullah Khan have established protocols for the generation of BMOs and demonstrated their applications in disease modeling. Here, we review the critical steps in BMO generation, their structural/ functional validation and discuss how BMOs can be applied to model inflammatory responses, rare genetic bone marrow failure syndromes, and multiple myeloma. These advances demonstrate BMOs' growing potential as powerful tools in hematopoietic research and will pave the way for further innovation and increasingly refined systems in future studies.

Regenerative medicine increasingly relies on therapeutic cells such as mesenchymal stem cells (MSCs), induced pluripotent stem cells (iPSCs), and engineered cellular constructs to repair and restore damaged tissues. However, clinical translation is constrained by challenges in maintaining viability, ensuring precise localization, achieving durable engraftment of transplanted cells, and producing enough clinically relevant cells at scale. Microfluidic technologies are emerging as transformative tools to address these barriers by enabling precise manipulation of fluids, biomaterials, and cells at the microscale. In the context of therapeutic cell delivery, these platforms can improve early retention and engraftment compared with conventional needle injection, tighten control over delivered cell dose, preserve viability under defined shear conditions, enable site-specific placement of cell-laden carriers, and support immunoisolating or immunomodulatory architectures that enhance immune safety. These platforms provide controlled microenvironments that mimic native tissue architecture, regulate biochemical and mechanical cues, and support scalable production of cell-laden carriers. Advances in microfabrication, from soft lithography and thermoplastics to 3D printing and hydrogel integration, have expanded device versatility, while embedded sensors allow real-time monitoring of cell state, metabolism, and differentiation. Beyond single-cell delivery, microfluidics facilitates encapsulation, co-culture, and organoid assembly, enabling multicellular systems with physiologically relevant interactions. Coupled with CRISPR genome editing and synthetic biology, these platforms allow the engineering of "smart" therapeutic cells with enhanced regenerative and immunomodulatory functions. Applications extend to microfluidic sorting for stem cell purification, controlled differentiation, and advanced manufacturing of immune cell therapies such as Chimeric Antigen Receptor (CAR)-T cells, alongside exosome-based strategies for precision delivery. Despite promising progress, obstacles remain in regulatory standardization, large-scale manufacturing, and integration with clinical workflows. This review highlights state-of-the-art microfluidic approaches for controlled delivery of stem cells and engineered cells, emphasizing how these systems impact key delivery metrics such as retention, dose control, shear resilience, spatial targeting, and immune interfaces to advance precision and personalized regenerative medicine.

Dormant cancer stem cells (CSCs) are the root cause of the drug resistance and metastatic processes of malignant tumors, but an in-depth analysis of their biological mechanisms is needed. Dormant CSCs are in the G0 phase of the cell cycle and are characterized by enhanced autophagic activity, a stable genomic structure and strong plasticity. Recently, several new specific markers of dormant CSCs, such as p27, CD13, QSOX1, Survivin, GPD1 and BEX2, have been identified, which offer hope for targeted therapy. In addition, epigenetic modifications such as DNA methylation and histone modifications have been reported to regulate the transition between the quiescent and proliferative states of dormant CSCs. From a clinical perspective, keeping cancer stem cells in a dormant state is helpful for preventing tumor recurrence and metastasis. To this end, clarifying the potential mechanisms and molecular regulation of cancer stem cell dormancy is vital. Here, in this review, we examine recent significant findings regarding tumor stem cell dormancy in both experimental and human disease models, emphasizing the underlying molecular mechanisms, regulatory processes, experimental models, and prospective research directions aimed at advancing this field and enhancing clinical translation.

Ameloblastoma is a benign odontogenic tumor with an aggressive growth phenotype orchestrated by a complex and heterogeneous tumor microenvironment. This review addresses how tumor cells, cancer-associated fibroblasts, mesenchymal stem cells, endothelial cells, and immune cells interact with non-cellular elements especially the extracellular matrix and hypoxic niches to drive invasive growth and recurrence. Several genetic changes associated with ameloblastoma activate mitogen-activated protein kinase (MAPK), Hedgehog (HH), Wnt/β-catenin, and less commonly PI3K/AKT signaling pathways. These pathways increase matrix-degrading enzymes such as matrix metalloproteinases and heparanase and reorganize collagen to create paths for local spread of ameloblastoma cells. Hypoxic niches in ameloblastoma stabilize hypoxia-inducible factor (HIF-1)α and activate vascular endothelial growth factor (VEGF) thereby linking low oxygen tension to new blood vessel growth within the microenvironment. Crosstalk between ameloblastoma epithelium and stroma through interleukin-6, transforming growth factor (TGF)-β, and connective tissue growth factor (CTGF) activates a positive feedback loops that stiffen the extracellular matrix and promote collective invasion. Within the encompassing jaw bone, a higher receptor activator of nuclear factor kappa-Β ligand/osteoprotegerin (RANKL/OPG) ratio and parathyroid hormone-related protein (PTHrP) level stimulate osteoclastogenesis, which accounts for the characteristic osteolysis displayed by ameloblastoma. Additionally, PD-L1 expression in ameloblastoma weakens T-cell activity in spite of the high population of M1 macrophages at the tumor leading edge. Collectively, coordinated interplay of these molecular processes define the invasive and aggressive growth phenotypes of ameloblastoma. Opportunities abound for development of targeted therapies for management of ameloblastoma. Potential candidates are inhibitors of BRAF/MEK and smoothened (SMO) gene/HH pathways, interruption of the TGF-β-Cancer-associated fibroblast axis, anti-angiogenic strategies, immune checkpoint blockade, and RANKL-directed therapy.

Background and objectives Atherosclerosis is a chronic disease marked by the build up of lipids and inflammatory cells in arterial walls, leading to vessel narrowing and increasing the risk of serious complications like heart attack and stroke. Recent findings suggest that microRNAs (miRNAs) serve as key regulators in the mechanisms driving atherosclerotic disease. However, the expression levels and functional roles of miRNA-133a-3p and miRNA-124-3p in atherosclerosis remain incompletely understood. The aim of this study was to determine the relationship between the expression levels of miR-124-3p and miR-133a-3p, and the phenotypic changes of S100A4-positive vascular smooth muscle cells in atherosclerosis. Methods We collected tissue samples from 25 patients with atherosclerosis who underwent coronary artery bypass graft surgery. IMA tissues were used as controls; atherosclerotic aortic tissues as cases. Expression levels of miRNAs were assessed using reverse transcription polymerase chain reaction (RT-PCR). Tissue samples underwent immunohistochemical staining with S100A4 protein to evaluate cellular and structural characteristics. Results A marked decrease in the expression of miR-133a-3p and miR-124-3p was observed in the atherosclerosis group compared to the control group, and both differences were statistically significant (P=0). Additionally, an increase in S100A4 protein immunoreactivity was detected in the atherosclerosis group. Interpretations and conclusions The downregulation of miRNA-133a-3p and miRNA-124-3p in atherosclerotic tissues, along with the observed increase in S100A4 protein immunoreactivity, suggests that these two miRNAs may play a role in the regulation of inflammatory endothelial phenotypes. Therefore, the interaction between miRNA-133a-3p, miRNA-124-3p, and S100A4 protein may help elucidate a potential mechanism underlying the prevention of atherosclerosis.

Chronic non-healing wounds pose a significant clinical challenge, driven by dysregulation of the "inflammation-immune-microbiome" triad. Traditional "debridement-anti-infection-coverage" approaches fail to break the vicious cycle of dysbiosis and immune dysfunction. Leveraging structural diversity and bioactivity, natural polysaccharides provide a versatile platform for multi-targeted intervention. This review systematically explores the mechanisms through which polysaccharides modulate the wound immune microenvironment, restructure microbial communities, and facilitate barrier repair. This interaction enables precise regulation of macrophage polarization, particularly the promotion of the M2 phenotype, as well as neutrophil function and adaptive immunity, thereby alleviating chronic inflammation. Moreover, polysaccharides utilize a variety of mechanisms to impact the microbiome, including direct antimicrobial effects through electrostatic interactions and prebiotic support that promotes the colonization and metabolism of beneficial bacteria. This review also explores advancements in intelligent delivery systems, such as microenvironment-responsive hydrogels, discusses challenges in clinical translation, and considers future directions that incorporate single-cell multi-omics, microbiota-based personalization, organ-on-a-chip models, and phage-polysaccharide synergistic therapies. This work offers a theoretical foundation and translational perspective for the development of next-generation polysaccharide-based strategies for chronic wound management.

CAR T cell therapy has demonstrated remarkable efficacy in treating haematological malignancies, including B-cell lymphomas, B-cell leukaemias, and multiple myeloma. CAR T cell therapy for acute myeloid leukaemia (AML) is also urgently needed. One of the major challenges is identifying AML-specific antigens, since many potential candidates (e.g. CD33, CD123, CLL-1, CD70, TIM-3 and FLT3) are also expressed on normal haematopoietic progenitors. This can lead to 'on-target/off-tumour' toxicity and bone marrow aplasia. CAR NK cell therapy for AML shows promise as a lower-toxicity, off-the-shelf alternative. NK cells have a lower inherent risk of GVHD and may cause milder CRS/ICANS. In this review, we will describe the current status of CAR T/NK cell development for AML. We will also introduce a new CAR T-cell or NK-cell therapy that targets mismatched HLA-DRB1 in patients with AML who have relapsed following an allogeneic haematopoietic stem cell transplant.

Melanocyte stem cells (McSCs) are a crucial melanocyte reservoir within the hair follicle niche. This review provides an overview of the processes for McSC quiescence and activation. Because McSCs closely interact with hair follicle stem cells, we have focused on this interaction. Given the high prevalence of hair graying, the McSC system serves as a model for cellular aging. Here, we highlight current research on the mechanisms of hair graying.

Iron metabolism is increasingly recognized as a key player in the development and progression of various cancers. Iron is required for vital cellular processes such as energy production; however, it can also interact with reactive oxygen species to cause cellular toxicity. Consequently, a host of proteins coordinate iron homeostasis, and ferritin stands out as a promising therapeutic target due to its pivotal role in buffering cellular iron levels. This review explores the relevance of ferritin in brain cancers, shedding light on how it influences the biology of both tumor cells and cancer stem cells (CSCs), a population of tumor cells that is notable in their resistance to conventional treatment strategies. Ferritin plays a critical role in protecting against oxidative stress and boosting resistance to ferroptosis, a form of cell death often evaded by CSCs. Development of cutting-edge strategies designed to target ferritin, including ferritinophagy-inducing compounds and novel redox-based therapies that can capitalize on the iron dependency of CSCs is discussed in context. We propose that the iron addiction of brain cancer cells provides a specific susceptibility, whereby removing their iron buffering mechanism via targeting of ferritin can result in favorable treatment outcomes, including the induction of iron-dependent cell death. Future studies on the modulation of ferritin offer a ground-breaking therapeutic strategy to undermine CSC-driven tumor growth, overcome resistance to conventional therapies, and ultimately improve treatment outcomes for patients battling brain cancers.

Dental tissues development involves two distinct cell lineages: mesenchymal cells (derived from the cranial neural crest) and epithelial cells (derived from oral ectoderm and pharyngeal epithelium). Emerging evidence highlights the remarkable functional heterogeneity of cranial neural crest-derived dental mesenchymal stem cells (DMSCs), exhibiting pluripotency, self-renewal, and differentiation capacities. This heterogeneity enables a single DMSC population to generate specialized subpopulations with unique roles in teeth and periodontal tissues formation. Significant progress has been made in characterizing six major types of DMSCs and two populations of closely related cells: Tooth germ progenitor cells (TGPCs) and dental follicle stem cells (DFSCs), critical during early morphogenesis; Stem cells from human exfoliated deciduous teeth (SHEDs) and apical papilla stem cells (SCAPs), pivotal for root development; Dental pulp stem cells (DPSCs), periodontal ligament stem cells (PDLSCs), gingival mesenchymal stem cells (GMSCs) and alveolar bone mesenchymal stem cells (ABMSCs), essential for maintaining and regenerating mature dental tissues. A key breakthrough has unveiled the development and hierarchy of DMSCs by applying new techniques like single-cell RNA sequencing (scRNA-seq). To integrate insights into the development of teeth and periodontal tissues, this review synthesizes current knowledge on both developmental heterogeneity and subpopulation heterogeneity within DMSCs and related cells. These insights not only advance fundamental understanding of the developmental mechanisms of teeth and periodontal tissues, but also establish a promising framework for achieving more efficient tissue regeneration and repair engineering.

Diseases associated with obesity and metabolic dysregulation, such as diabetes and metabolic dysfunction-associated steatotic liver disease (MASLD) promote chronic low-grade inflammation, which in turn, may enhance the risk for cardiovascular disease. Emerging evidence in recent years suggests that chronicity of inflammation involves alterations in bone marrow homeostasis. Obesity-related inflammation and metabolic stress, including hyperglycemia or hyperlipidemia, may trigger rewiring of hematopoietic stem and progenitor cells (HSPCs) in the bone marrow, driving production of myeloid cells with heightened inflammatory capacity that in turn fuel and sustain chronic inflammation. This process is akin to trained immunity and may promote an inflammatory memory that links metabolic disorders to their cardiovascular complications. Clonal hematopoiesis of indeterminate potential (CHIP) is characterized by aging-related emergence of somatic mutations in hematopoietic cells that clonally expand and bear higher inflammatory potential. Importantly, a bidirectional link between CHIP and metabolic disorders as well as their cardiovascular sequelae emerges. Here, we review current concepts regarding the links between bone marrow biology and metabolic diseases and associated chronic inflammation.

Post-traumatic stress disorder (PTSD) is a debilitating neuropsychiatric condition triggered by severe trauma, characterised by dysregulated fear circuitry, hippocampal atrophy with impaired neurogenesis, chronic neuroinflammation, neuroendocrine dysregulation, and disrupted prefrontal-limbic connectivity. Existing treatments are largely symptomatic, failing to address underlying neurobiological deficits. Emerging regenerative approaches using human stem cells, particularly induced pluripotent stem cell-derived neural progenitor cells (iPSC-NPCs), human embryonic stem cells (hESCs), mesenchymal stem cells (MSCs), and their extracellular vesicles (EVs), offer mechanistic plausibility for neural repair via direct neuronal replacement, paracrine neurotrophic support (e.g., BDNF, GDNF, VEGF), immunomodulation (e.g., shifting microglia to anti-inflammatory phenotypes), and promotion of synaptic plasticity and epigenetic reprogramming. Preclinical evidence remains limited and largely indirect, with sparse PTSD-specific studies (e.g., one report of iPSC-NPC transplantation reducing fear behaviour and enhancing hippocampal BDNF/neuronal density in a rat model) supplemented by convergent data from adjacent CNS injury paradigms. MSC- and iPSC-derived EVs, enriched with regulatory miRNAs (e.g., miR-124, miR-21, miR-146a), emerge as a safer, cell-free alternative with strong immunomodulatory potential and greater translational feasibility. However, reproducibility is constrained by model variability, lack of independent replication, and absence of PTSD-focused clinical trials. Major challenges include tumorigenicity risks (especially for pluripotent-derived cells), immune rejection, epigenetic/genomic instability, manufacturing scalability, stringent regulatory requirements, and elevated ethical thresholds for invasive therapies in a non-lethal psychiatric disorder. This review examines how stem cell actions align with PTSD brain changes, critically assesses the limited evidence, and suggests a careful translational plan.

Dermatoporosis (DP) or chronic cutaneous fragility syndrome has traditionally been linked to extracellular matrix (ECM) dehydration, reduced cellular turnover, epidermal thinning, and vascular fragility. However, recent imaging methods and clinical evidence indicate that the dermoepidermal junction (DEJ) might be the earliest change reflecting DP reversal.

High mobility group box 3 (HMGB3) acts as an essential participator in fundamental biological processes, including transcriptional regulation, chromatin remodeling and DNA repair. HMGB3 is highly expressed and functionally essential during embryonic development, particularly in the hematopoietic and nervous systems, but it is significantly downregulated or silenced in most normal adult tissues. Its aberrant upregulation has been revealed in numerous human malignancies, such as leukemia, as well as breast, bladder, colorectal and gastric cancer, and its expression levels have been established to be closely associated with poor prognosis of specific patients. Accordingly, the present review systematically explores the central roles of HMGB3 in mediating resistance to cancer therapy. This review focuses on its multifaceted mechanisms of maintaining cancer stemness, enhancing DNA damage repair, modulating cell death pathways and remodeling the tumor microenvironment, thereby contributing to the resistance to chemotherapy, radiotherapy, targeted therapy and immunotherapy collectively. HMGB3 can be accepted as a key target in the development of highly promising therapeutic strategies, given its pivotal involvement in multidrug resistance, which may offer novel avenues for overcoming clinical treatment resistance and improving patient outcomes.

Mesenchymal stem cell‑derived extracellular vesicles (MSC‑EVs) have garnered research attention due to their unique biological functionalities and therapeutic potential. Compared with the parent MSCs from which they originate, MSC‑EVs are typically free from systemic allergic reactions, hemolysis, pyrogenic reactions, abnormal hematological changes, and vascular and muscle irritation problems, and thus, exhibit therapeutic potential. The present review provides a comprehensive analysis of numerous isolation methodologies for MSC‑EVs, with each method being evaluated based on key parameters, including principles, advantages, limitations and applications. Notably, the therapeutic potential of MSC‑EVs in the treatment of tuberculosis (TB) has been emphasized. MSC‑EVs have demonstrated unique capacities to modulate the T helper cell (Th)1/Th2/T regulatory cell balance, promote M2 macrophage polarization, alleviate inflammation through microRNA‑mediated mechanisms and enhance host defense through antimicrobial peptide responses. The integration of MSC‑EVs with anti‑TB therapy can improve lung, kidney and bladder health by reducing TNF‑α levels and increasing IL‑10/TGF‑β ratios. Notably, functional discrepancies between EVs derived from distinct MSC sources, such as umbilical cord vs. bone marrow cells, underscore the need for targeted optimization strategies. Adequate risk assessment is important before clinical trials, particularly concerning immunogenicity, potential pro‑inflammatory effects and promotion of TB latency. The present review explores the potential clinical applications of MSC‑EVs in TB and other infectious diseases, offering key insights into their therapeutic potential, with the aim of guiding future research.

Glioblastoma (GBM) is a highly aggressive, therapy-resistant brain tumor with inevitable recurrence despite maximal multimodal treatment. Increasing evidence suggests that this intractability arises from coordinated cellular programs rather than a single dominant pathway. Central to these programs are glioma stem-like cells (GSCs), which sustain self-renewal, phenotypic plasticity, and resistance to genotoxic and metabolic stress, and yet the molecular basis of their long-term tumor-propagating capacity remains incompletely understood. Here, we synthesize recent advances to propose an integrated conceptual framework-the Triadic Nexus-in which GSC stemness, telomere maintenance mechanisms, and metabolic reprogramming function as a self-reinforcing regulatory system. We review how telomerase reactivation versus alternative lengthening of telomeres (ALT) differentially shape genomic stability, immune signaling, and metabolic states and how metabolic plasticity feeds back to regulate stemness and telomere-associated stress responses. Drawing on single-cell, spatial, and multi-omics studies, we highlight how these interdependent axes collectively sustain therapy resistance and tumor recurrence. Finally, we discuss the translational implications of the Triadic Nexus, emphasizing rational combinatorial therapeutic strategies and biomarker-guided patient stratification based on telomere and metabolic signatures. By unifying stemness, telomere biology, and metabolism into a mechanistically testable model, this review provides a systems-level framework for understanding GBM persistence and guiding next-generation therapeutic interventions.

Focal post-traumatic cartilage lesions frequently progress to early osteoarthritis, highlighting the limited regenerative capacity of adult articular cartilage. Compared to native tissue, conventional surgical interventions often produce fibrocartilage with inferior biomechanical properties, representing a persistent therapeutic challenge. This review assessed preclinical studies exploring cartilage repair strategies using autologous mesenchymal stem cells (MSCs) in animal models. MSCs therapies demonstrated superior cartilage regeneration, matrix organization, and integration into the surrounding tissue compared to the control groups. The most efficient source was found to be bone marrow - derived mesenchymal stem cells (BM-MSCs) combined with biodegradable scaffolds, suggesting their potential in tissue engineering applications. Despite methodological heterogeneity across studies - including variations in stem cells sources, implant types, and deliver strategies - cumulative evidence strongly supports the regenerative potential of autologous MSCs for cartilage repair. Current research identifies key knowledge gaps, including the absence of standardized experimental protocols and limited insight into the mechanisms of tissue remodeling and maturation. Collectively, these gaps limit direct clinical translation, highlighting the need for further, standardized studies in large animal models with long-term follow-up (>2 years) to assess integration, functional maturation, and the full regenerative potential of the repair tissue.

Dental follicle stem cells (DFSCs) originate from the dental follicle during tooth development and possess multilineage differentiation potential, contributing to periodontal tissue regeneration, bone repair, and immunomodulation. This review highlights the recent advances in the application of DFSCs and biological scaffolds for regenerative medicine, with a focus on oral and craniofacial tissue. DFSCs exhibit key advantages for regenerative therapies, including high accessibility, robust self-renewal capacity, and multipotent differentiation potential, enabling their differentiation into odontogenic (dentin- and enamel-forming), osteogenic, and fibroblastic lineages. We discuss the embryonic origin of DFSCS and their unique ability to maintain stable cellular properties in long-term in vitro culture. Importantly, DFSCs play a pivotal role in tooth morphogenesis, periodontal tissue formation, and craniofacial bone regeneration, making them promising for functional oral tissue restoration. A critical aspect of DFSC-based regeneration is the integration with bioactive scaffolds, which provide structural support, promote cell adhesion, proliferation, and differentiation, and facilitate vascularization. We analyze how scaffold properties, such as biodegradability, porosity, and permeability, influence DFSC behavior and therapeutic outcomes. Finally, we explore future challenges and opportunities in optimizing DFSC-scaffold interaction, emphasizing advancements in biomaterial design and emerging bioengineering technologies. Preliminary evidence suggests that integrating DFSCs with engineered scaffold systems may offer potential benefits for personalized regenerative therapies, though further validation is required before clinical translation. Such approaches could contribute to advancing tooth and craniofacial reconstruction strategies. This review consolidates existing insights and explores potential avenues for future research to support advancements in DFSC-based regenerative medicine.