Systemic sclerosis (SSc) is an autoimmune condition affecting several organs. It is identified by thickening of the dermis, connective tissue affected by collagen accumulation, and vascular injuries that induce hypoxia. The present study aimed to determine whether extracellular vesicles (EVs) from adipose-derived stem cells (ADSCs) attenuated bleomycin-induced skin fibrosis and oxidative stress in scleroderma. ADSCs and their EVs were separated and a bleomycin-induced SSc mouse model was constructed. High-throughput sequencing was employed to study abnormal expression of circular RNAs in SSc skin tissues with or without ADSC-EV treatment. The regulatory mechanism and targets were studied using bioinformatics analysis, luciferase reporting analysis, angiogenic differentiation experiments, and RT-qPCR detection analysis. EVs from ADSCs were successfully isolated. The exosome treatment prevented dermal thickening and fibrosis in bleomycin-induced scleroderma. In addition, circ-Zfyve9 was demonstrated to have an important function in ADSC-EV-mediated skin tissue protection. GPX4 and miR-135 were shown to be downstream targets of circ-Zfyve9. Overexpressing miR-135 or downregulating GPX4 reversed the promotion effects of circ-Zfyve9 on angiopoiesis by increasing lipidosome ROS in EPCs under hypoxic conditions. Overexpressing miR-135 or downregulating GPX4 reversed the inhibition effect of circ-Zfyve9 on fibrosis in myofibroblasts under hypoxic conditions. Overexpressing circ-Zfyve9 increased the therapeutic effect of ADSC-EVs. EVs from ADSCs attenuated bleomycin-induced skin fibrosis and oxidative stress in scleroderma via circ-Zfyve9 delivery.

Cardiovascular diseases remain the leading global cause of mortality, highlighting the need for improved early detection and targeted interventions. Extracellular vesicles (EVs) are nano-sized, bilipid-layered particles released by all cell types that carry RNAs, proteins, lipids, and metabolites reflective of their parent cells. They mediate intercellular communication by transferring cargo that alters recipient cell transcriptomic and proteomic states, and this property may be leveraged for therapeutic delivery. This review provides a comprehensive, cardiovascular disease-focused synthesis of EV biology with emphasis on what is clinically actionable and mechanistically novel. The review describes EV biogenesis and their multiomic cargo composition, followed by tissue-resolved and cell type-resolved EV signaling across cell types relevant to cardiovascular disease. A dedicated section addresses EV-mediated interorgan crosstalk across the heart-kidney, heart-liver, brain-heart, and adipose-heart axes as a systems-level framework for cardiometabolic disease. We next turn to translational applications, describing EV cargo composition under pathological conditions with implications for disease-related signaling and the potential for biomarker development. For liquid biopsy applications, the review introduces a 3-tier evidence framework classifying circulating EV biomarkers by clinical validation status, supported by a practical preanalytical checklist for cardiovascular plasma studies. Engineered, stem cell-derived, and RNA-loaded EV therapeutic modalities are evaluated, and active clinical trials are catalogued along with key challenges in cargo loading, biodistribution, immunogenicity, and regulatory standardization. We conclude with a structured future directions and perspectives section identifying the most tractable open questions required to advance EVs from discovery to cardiovascular clinical practice.

Smoking cessation decreases lung cancer progression; however, its effects on precancerous lesions and the underlying mechanisms remain unclear. This study established a mouse model of precancerous pulmonary nodules and employed single-cell RNA sequencing (scRNA-seq) and immune repertoire sequencing (IR-seq) to elucidate the regulatory mechanisms by which smoking cessation influences the development of lung precancerous lesions.

Rapid endothelialisation is crucial for developing hemocompatible vascular grafts for coronary artery disease. This bibliometric analysis maps the research landscape of endothelial cells and endothelialisation in tissue-engineered vascular grafts (TEVGs) to identify evolving trends and surgical relevance.

MicroRNAs (miRNAs) regulate gene expression and generate isoforms (isomiRs) with distinct targeting properties, but their roles in cellular specification and reprogramming remain poorly understood. Here, we investigated miRNAs and isomiRs during direct reprogramming to conventional type 1 dendritic cells (cDC1s), identifying miR-124 and miR-142 as facilitators of the process. The canonical miR-124-3p strand induced a permissive chromatin landscape enriched for cooperative transcription factor motifs, thereby transiently increasing reprogramming efficiency. In contrast, miR-142 enhanced lineage fidelity by repressing fibroblast identity and activating cDC1-specific programs through cooperating isomiRs that drove XCR1 expression and increased type 3 interferon production. In addition, miR-142 mimics enhanced cancer cell reprogramming and anti-tumor immunity in vivo. Finally, we developed RNA-based cDC1 reprogramming using transcription factor mRNAs combined with miRNA mimics. Together, these findings uncover miRNA isoform diversity as a programmable regulatory layer in immune cell specification and establish RNA-driven reprogramming as a non-viral strategy for cancer immunotherapy.

Despite evidence highlighting immunoregulatory roles of tuft cells, it is not known whether vitamin A or retinoic acid affects tuft cell homeostasis. Here, we find that epithelial-intrinsic retinoic acid receptor regulates tuft cell numbers in mice. However, loss of retinoic acid signaling in tuft cells does not replicate this effect, suggesting altered differentiation. Consistent with this, retinoic acid administration to stem cell-derived organoids reduces tuft cell numbers, and epithelial-intrinsic retinoic acid is sufficient to alter tuft cell responses. In addition, dietary vitamin A dynamically alters tuft cells in vivo and regulates anti-helminth immunity in a tuft cell-dependent manner. Mechanistically, epithelial retinoic acid signaling promotes expression of Sprouty2, a negative regulator of tuft cell differentiation. Furthermore, stem cell-specific Sprouty2 disruption abrogates vitamin A regulation of tuft cells. Collectively, these data indicate that retinoic acid restricts tuft cell differentiation and carries important implications for how vitamin A affects intestinal health and immunity.

Spinal cord injury (SCI) induces neuroinflammation predominantly mediated by microglia, thereby establishing a detrimental milieu that impedes neurological recovery. Extracellular vesicles (EVs) derived from umbilical cord mesenchymal stem cells (UCMSCs) possess considerable therapeutic potential; however, their clinical translation is constrained by insufficient bioactivity, poor targeting specificity, and uncontrolled release kinetics. Here, we present a multidimensional engineering strategy that overcomes these barriers synergistically. Tetramethylpyrazine (TMP)-pretreated extracellular vesicles (TEVs) are enriched with anti-inflammatory and pro-regenerative factors in their cargo, while Angiopep-2 (Ang2) peptide-modified TEVs (Ang-TEVs) confer significantly enhanced microglial targeting. A reactive oxygen species (ROS)-responsive hyaluronic acid (HA)-phenylboronic acid (PBA)/polyvinyl alcohol (PVA) hydrogel serves as an intelligent depot for sustained, on-demand Ang-TEVs release at the lesion site. This construct, Ang-TEVs@Gel, demonstrated robust lesion accumulation and selective microglial uptake. It delivered miR-664a-3p, which suppressed PIK3CA to attenuate PI3K-AKT-mTOR signaling and unleash autophagic flux, reprogramming microglia toward a reparative state that enhanced myelin debris clearance and quelled inflammation. Consequently, axonal regeneration and remyelination were markedly improved, driving significant motor recovery in SCI mice. By integrating preconditioning, active targeting, and stimuli-responsive biomaterials, this strategy provides an elegant blueprint for engineering EV-based therapies to repair the injured central nervous system.

Burn wound healing remains a major clinical challenge. Mesenchymal stem cell-derived extracellular vesicles engineered to deliver defined microRNA cargo or modulate endogenous microRNA profiles have emerged as promising cell-free therapeutics, but native extracellular vesicle preparations remain constrained by low yield, heterogeneity, insufficient targeting, and incomplete cargo control. Moreover, much of the current evidence still comes from non-burn wound models. This review presents a burn-oriented framework that aligns upstream parental-cell programming, downstream vesicle modification, and biomaterial-assisted delivery with key burn-specific barriers, including burn depth, eschar, infection, hypoxia, systemic inflammation, inhalation injury, grafting requirements, and temporal immune dysregulation across the systemic inflammatory response syndrome-to-compensatory anti-inflammatory response syndrome transition. We also discuss translational requirements that are often underemphasized in general wound-healing reviews, including dose scaling for large total body surface area burns, repeat application, compatibility with debridement and grafting, storage and thawing in burn centers, sterility, use in infected wounds, and whether local extracellular vesicle delivery can mitigate systemic dysfunction. Overall, microRNA-engineered extracellular vesicles are a versatile platform for burn wound repair; however, clinical translation remains speculative without large-animal, infected-burn, grafting, long-term scar, and human safety data.

Fish oogonial stem cells (OSCs) are vital for fish reproduction research and germplasm conservation, yet stable long-term in vitro culture of fish OSCs remains a major technical bottleneck. Herein, we established an efficient in vitro culture system (termed L15SP) for OSCs derived from Paralichthys olivaceus, consisting of L-15 medium supplemented with15% fetal bovine serum (FBS), 2 μg/L basic fibroblast growth factor (bFGF), 2 μg/L leukemia inhibitory factor (LIF), 50 μmol/L β-mercaptoethanol (β-ME), 1% fish serum, and 18 g/L embryo extract protein, cultured at 23 °C. This system enabled stable long-term passage of P. olivaceus OSCs. Further investigations revealed that interferon-induced transmembrane protein 3 (Ifitm3) was highly expressed on the membrane of P. olivaceus OSCs. Functional assays demonstrated that Ifitm3 significantly enhanced proliferation, migration, and stemness maintenance of long-term cultured OSCs. Ifitm3 positively modulated the expression of key PI3K-AKT signaling components, including pik3cb, pik3r1, and akt2, to regulate downstream OSC functional genes. Upon pathway activation, Ifitm3 facilitated PIP3 enrichment at the OSC plasma membrane, thereby amplifying PI3K-AKT signaling. In conclusion, Ifitm3 governed OSC biological functions by potentiating PI3K-AKT signal transduction. This study establishes a reliable long-term culture system for fish OSCs and identifies a novel functional marker for OSC identification, providing valuable support for fish germplasm preservation and genetic breeding.

Anisotropic titanium nano-surfaces produced by alkali etching exert diverse biological effects through physicochemical cues derived from anisotropically distributed nanospikes. These effects can be further enhanced by hierarchically superimposing nanostructures onto micro-roughened surfaces. This study aimed to investigate the effects of micro/nano three-dimensionally hierarchical titanium surfaces on the osteoblastic functions and osseointegration of dental implants. Three-dimensionally nano-roughened titanium surfaces fabricated using a combination of hot acid and alkaline treatments showed a higher density and anisotropic distribution of nanospikes than that on conventional nano-roughened surfaces, while exhibiting key physicochemical features similar to those of conventional nano-roughened surfaces, including superhydrophilicity and negative surface potential associated with surface hydroxyl groups. These three-dimensionally nano-roughened surfaces significantly enhanced bovine serum albumin adsorption. They also promoted the proliferation and osteoblastic differentiation of mouse bone marrow stromal cells compared with conventional micro-roughened or nano-roughened titanium surfaces. In vivo, titanium implants with three-dimensional nano-surfaces showed significantly greater osseointegration strength than that of micro-roughened implants when placed in the rat maxillary molar region. This enhancement was associated with enhanced early bone formation and increased contact and distant osteogenesis. Exploratory association analysis suggested that the composite topographical descriptor reflecting nanospike density and spatial heterogeneity was associated with increased albumin adsorption under controlled in vitro conditions. Collectively, micro/nano three-dimensionally hierarchical titanium surfaces are associated with enhanced early osseointegration and promoted osteoblastic differentiation, highlighting their potential for advanced implant surface design.

Cancer stem cells (CSCs) constitute a rare yet highly adaptable tumour subpopulation that drives tumour initiation, intratumorally heterogeneity, metastasis, recurrence, and therapy resistance. Emerging evidence indicates that mitochondrial dynamics and mitochondrial ion signalling form an interconnected regulatory network that enables CSCs to remodel their metabolic and signalling states in response to environmental and therapeutic stress. Mitochondrial architectural remodelling through fission, fusion, biogenesis, and mitophagy cooperates closely with mitochondrial Ca2+ signalling and ion transport systems, including the mitochondrial calcium uniporter (MCU), voltage-dependent anion channels (VDACs), and mitochondrial K+ channels, to regulate mitochondrial membrane potential, oxidative phosphorylation (OXPHOS), reactive oxygen species (ROS) signalling, and bioenergetic adaptation. Selected plasma membrane and ER-associated ion channels further contribute by modulating mitochondrial signalling pathways. Together, these processes govern CSC plasticity, adaptive stress tolerance, and stemness-associated programs, facilitating survival under hypoxia, nutrient deprivation, and anticancer therapy. In this review, we explore how mitochondrial dynamics and ion signalling converge to shape CSC metabolic flexibility and therapeutic resistance. We further discuss emerging diagnostic and therapeutic opportunities targeting mitochondrial dynamics-ion signalling crosstalk, while highlighting key challenges, including CSC heterogeneity, metabolic adaptability, and the need for selective strategies capable of eliminating CSCs while sparing normal stem-cell populations.

Tendon-bone interface (TBI) injuries, typified by rotator cuff tears, are common musculoskeletal disorders. Their intrinsic healing capacity is limited by pathological conditions such as local hypoxia, oxidative stress, and secondary fatty infiltration, which prevent spontaneous restoration of the native four-zone gradient architecture. As a result, functional tissue is often replaced by fibrovascular scar tissue with inferior mechanical properties. Because surgical repair alone cannot precisely recreate this complex interface, highly biomimetic tissue-engineered regenerative strategies have emerged as a promising alternative. Beginning with the anatomy of the rotator cuff and the key challenges in treating rotator cuff injuries, this review summarizes the spatiotemporal complexity, physiological vulnerability, and rehabilitation challenges of the TBI. It further discusses the structural composition, fabrication methods, mechanisms of action, and clinical applications of tissue-engineered strategies for TBI regeneration. These approaches use scaffolds based on hydrogels, decellularized matrices, polymers, collagen, and nanoparticles, which can be functionally engineered through graded architectures, aligned structures, mineralization cues, and tailored interfacial properties. In parallel, active components such as stem cells, exosomes, and bioactive factors can be incorporated to recreate a three-dimensional microenvironment that supports tissue regeneration, attenuates inflammation, regulates bone metabolic homeostasis, and promotes vascular regeneration. Although substantial progress has been made in tissue-engineered repair of rotator cuff injuries, future studies should place greater emphasis on digitally enabled and coordinated scaffold design, more robust safety assessment, and quantitative evaluation of therapeutic efficacy. Mechanistic studies and translational research will also be essential to bridge the gap between basic research and clinical application.

Nephrotoxicity is a major clinical concern because it can impair kidney function through inflammation and apoptosis. This study aimed to evaluate the effects of mesenchymal stem cell (MSC)-derived secretome on cyclooxygenase-2 (COX-2) and caspase-3 levels in a rat model of doxorubicin-induced nephrotoxicity.

Osteoporosis is associated with reduced active vitamin D, but the molecular basis remains incompletely understood. This study investigated how active vitamin D preserves skeletal homeostasis and prevents bone loss.

Glioblastoma (GBM) is a highly lethal brain cancer in which the calcitonin receptor (CT Receptor), encoded by the CALCR gene, is expressed in 78-88% of patient biopsies. Here, we investigate whether the CT Receptor plays a role in cancer cell survival. In cancer cell lines, knockdown of CALCR disrupts the cell cycle and induces apoptosis, supporting an essential pro-survival role. The CALCR gene produces three main transcripts in humans, of which Transcript 1 encodes CALCRb mRNA including exon 10 and is translated into the CTb Receptor isoform, and Transcripts 2 and 3 which are translated into the CTa Receptor. CALCRb expression is conserved across a diverse range of mammalian species. We examined the expression of all CT Receptor isoforms (CALCRtotal) and CALCRb expression in four high-grade glioma stem-like cell lines and in U-87 MG glioblastoma cells. Using qPCR, we observed stable levels of both CALCRtotal and CALCRb expression under conditions of autophagy or apoptosis, consistent with a requirement for CALCRb in cell survival. As alternative splicing (AS) of key genes in cancers confers tumour resilience, we investigated AS of CALCR transcript 2 using long-read nanopore sequencing. Unexpectedly, we discovered a novel AS event causing inclusion of exon 10 within Transcript 2 in all glioblastoma cell lines investigated. This finding, together with stable CALCRb expression under cellular stress and the finding by other groups confirming that knockdown of CT Receptor compromises cell survival, implicates the CTb Receptor as a potential oncoprotein.

Primary non-response to anti-tumor necrosis factor (anti-TNF) therapy remains a major clinical challenge in ulcerative colitis (UC); however, public-data transcriptomic studies often yield unstable single-gene biomarkers and limited replication.

Preclinical evidence supports the potential use of human umbilical cord blood-derived mononuclear cells (hUCB-MNCs) for preterm infants with preterm birth-associated complications (PBAC). Allogeneic hUCB-MNCs could extend this therapeutic option to infants without autologous cord blood available at birth.

Myeloproliferative neoplasms (MPNs) are a group of hematologic malignancies for which current treatment options remain limited, underscoring the urgent need to explore novel therapeutic targets and intervention strategies. Through a high-throughput screen of an epigenetic compound library, we identified the SIRT6 allosteric agonist MDL-800 as a potent suppressor of neutrophil hyperplasia. We established an endogenous sirt6-mutant zebrafish model that develops a myeloproliferative neoplasm (MPN)-like phenotype, with a 64% incidence in adult zebrafish. Mechanistically, Sirt6 was found to regulate neutrophil proliferation in vivo and in vitro by deacetylating histone H3K9 at the c-myb promoter. Sirt6 deficiency led to aberrant proliferation of neutrophils and hematopoietic stem/progenitor cells, whereas Sirt6 overexpression significantly alleviated neutrophil hyperplasia and MPN-related symptoms. Furthermore, the SIRT6 activator MDL-800 enhanced the efficacy of imatinib and reduced neutrophil proliferation in a zebrafish leukemia model. In xenograft mouse models, the combination of MDL-800 and imatinib significantly inhibited leukemia progression and restored drug sensitivity in imatinib-resistant cases. This study establishes the Sirt6-c-Myb axis as a core epigenetic pathway for myeloid homeostasis, providing a novel strategy for simultaneously suppressing neutrophil hyperplasia and enhancing chemotherapeutic efficacy in hematologic malignancies.