Lipid abnormalities have been observed in brain, cerebrospinal fluid (CSF), and blood in association with late-onset Alzheimer's disease (LOAD). It is unknown which of these abnormalities are precursors to LOAD and which are concomitants of illness or its treatment. Inherent abnormalities can be identified in induced pluripotent stem cell (iPSC)-derived brain cells. These cells lack markers associated with aging and environmental exposures. The iPSC lines of patients with LOAD or healthy individuals were differentiated to astrocytes. Astrocytes are crucial to neural activity and health, and altered astrocyte functions are associated with LOAD pathology. Lipidomics analyses were performed on whole-cell and mitochondria-enriched fractions. Large reductions in cholesterol esters (CEs) and imbalances in fatty acids (FAs) were observed in LOAD-associated cells or their mitochondria. There were only modest differences in other lipid classes, including membrane structural lipids. The findings identify abnormalities in CEs, as well as in FAs, as inherent abnormalities and likely precursors to LOAD. These differences implicate mechanisms contributing to disease pathogenesis. Further study may lead to early interventions to prevent or delay LOAD.

Chimeric antigen receptor (CAR)-T cell therapy has achieved remarkable clinical success in B cell malignancies. However, its efficacy in solid tumors remains limited, in part due to suboptimal expansion, persistence, and restrained effector function. Strategies that promote durable CAR-T cell fitness are therefore required to overcome these barriers. In this study, we generated HER2-CAR-T cells targeting human breast cancer cells and evaluated the impact of different cytokine supplementation strategies on CAR-T cell phenotype and function. We analyzed gene expression patterns and performed repetitive tumor killing assays to assess the ability of CAR-T cells expanded with IL-2 + IL-7 + IL-15 compared with IL-2 alone to maintain proliferation and cytotoxic function across multiple rounds of tumor cell exposure. Compared with IL-2 alone, supplementation with IL-7 and IL-15 significantly enhanced CAR-T cell expansion, preserved stem cell-like features prior to antigen encounter, and promoted superior proliferative capacity. Moreover, CAR-T cells cultured with IL-7+15 or IL-2+7+15 maintained sustained cytotoxicity and exhibited increased antitumor cytokine production during repeated tumor challenges. Notably, IL-7 and IL-15 supplementation induced a CD57+ CAR-T cell population that, unlike the immunosenescent CD57+ cells reported previously, retained full proliferative and cytotoxic capacity, with CD57 expression being dynamically downregulated upon antigen stimulation. Collectively, these findings demonstrate that incorporation of IL-7 and IL-15 into CAR-T cell manufacturing protocols substantially improves expansion, persistence, and effector function, supporting their use as a strategy to enhance CAR-T cell performance against solid tumors.

Dogs represent a promising animal model for analyzing human neurodegenerative diseases, owing to their similarities to humans in nervous system architecture and behavioral phenotypes. Neural stem cells (NSCs) serve as a highly valuable in vitro experimental model for investigating neurogenesis, neurodegenerative disease pathogenesis, and neural molecular biology; however, studies on immortalized canine neural stem cell lines remain scarce. Herein, we successfully established an immortalized canine hippocampal neural stem cell line that can be continuously passaged in vitro via SV40 large T antigen (SV40LT) viral infection and subsequent cellular transformation. Both the immortalized NSCs and their normal parental counterparts differentiated into neuronal and glial lineages under induced differentiation conditions. Normal canine hippocampal NSCs can be passaged for no more than 10 generations, whereas the immortalized line can be passaged indefinitely while maintaining a normal karyotype. This immortalized canine hippocampal NSC line can act as a critical experimental tool for future research into neural differentiation mechanisms and stem cell-derived therapeutic strategies for neurological disorders in dogs.

Glioblastoma (GBM) is an aggressive human malignancy. Recent advances in GBM research have highlighted innovative therapeutic approaches, including the use of small molecules that eliminate GBM in mouse models. However, there are few reports on the restoration of lost neuronal functions in patients. Considering that GBM contains GBM-initiating cells (GICs) with characteristics of both cancer and neural stem cells, we investigated whether GICs could be redirected toward non-tumorigenic neurons to support the preservation of neural function in the brain with GBM. We demonstrated that the neuronal differentiation inducer Isoxazole 9 (ISX9) effectively induced GICs to differentiate into neurons, accompanied by significant changes in their gene expression profiles. The sequential application of ISX9 and the DHODH inhibitor brequinar (BRQ), which successfully eradicated undifferentiated GICs, not only promoted neuronal differentiation but also inhibited GIC tumorigenesis in the mouse brain, leading to prolonged survival and preservation of motor function in tumor-bearing mice. Furthermore, pathological analysis revealed that this combination not only reduced the size of GIC brain tumors but also facilitated the formation of synapse-like structural contacts between GIC-derived cells and host mouse neurons, suggesting remodeling of the tumor-neural interface within the tumor-developed area. Collectively, these findings suggest that the modulation of tumorigenic GIC differentiation may represent a strategy to preserve neural circuit integrity within the tumor-bearing brain.

ChemoNETosis represents a distinct form of therapy-induced innate immune activation, in which cytotoxic chemotherapy alters the tumor microenvironment (TME) in ways that attract and stimulate neutrophils, ultimately triggering the release of neutrophil extracellular traps (NETs). Unlike classical NETosis, which typically arises in response to infection or sterile inflammation, chemoNETosis is initiated by treatment-related danger signals and chemokine-cytokine loops that reshape the immune landscape and promote the formation of NET-rich metastatic niches. These NET structures serve not only as physical scaffolds but also as bioactive platforms enriched with proteases, reactive oxygen species, and enzymes capable of activating growth factors, collectively driving epithelial-mesenchymal transition, enhanced tumor cell plasticity, immune cell exclusion, changes in vascular permeability, and the development of chemotherapy resistance. While predominantly associated with tumor-promoting effects, chemoNETosis may, under specific genetic or metabolic conditions, contribute to antitumor responses, reflecting its context-dependent plasticity. In this review, we present what is, to our knowledge, the first in-depth synthesis of chemoNETosis across solid tumors, with a focus on key mechanistic nodes and translational perspectives.

Diabetes mellitus remains a leading cause of morbidity worldwide, driven in type 1 diabetes by autoimmune destruction of pancreatic β-cells and in advanced type 2 diabetes by progressive β-cell dysfunction and failure. Diabetes affects around 830 million people globally, with the vast majority residing within low- and middle-income nations. Over the last few decades, the numbers of people who have diabetes and those with untreated diabetes have consistently increased. Although current pharmacologic therapies improve glycemic control, they do not restore functional β-cell mass. Consequently, strategies aimed at protecting, regenerating, or replacing insulin-producing cells have emerged as a major focus of regenerative medicine. Stem cell-based approaches offer the potential to generate renewable sources of glucose-responsive β-like cells, but challenges remain in achieving full functional maturation, immune protection, scalable manufacturing, and durable clinical engraftment. This review examines advances in engineering stem cell-derived insulin-producing cells for islet replacement therapy, with an emphasis on differentiation strategies, immunoprotective approaches, and the translational barriers that must be addressed for durable β-cell replacement.

Mesenchymal stem cells (MSCs) sense biophysical cues from their microenvironment, which regulate cytoskeletal organization and the nuclear-cytoplasmic distribution of the mechanotransducer Yes-associated protein (YAP), thereby shaping cellular behavior. Prolonged ex vivo culture on non-physiologically rigid substrates induces persistent nuclear YAP localization, a phenomenon often referred to as mechanical memory. We therefore examined whether transient epigenetic modulation could modulate YAP subcellular localization in human bone marrow-derived MSCs. Treatment with the DNA methyltransferase inhibitor 5-azacitidine (5-Aza) shifted YAP localization toward the cytoplasm in MSCs, without overt changes in pluripotency marker expression or neural differentiation capacity. RNA sequencing revealed broad down-regulation of extracellular matrix (ECM)-related genes following 5-Aza treatment. Independent suppression of ECM production via TGF-β signaling similarly promoted cytoplasmic YAP localization. When subsequently transferred to soft substrates, 5-Aza-treated MSCs restored YAP relocalization despite prior expansion on stiff surfaces. Together, these findings suggest that transient 5-Aza treatment can partially alleviate mechanically induced YAP regulation associated with mechanical memory. Thus, simple and transient administration of 5-Aza may offer a practical means to improve the quality of MSCs during ex vivo expansion for cell-based therapies.

Background: During aging, skeletal muscle mass constantly diminishes and myogenic potential declines. At the cellular level, a decline in mitochondrial function is a hallmark of the aging process and the deficiency of the mitochondrial network contributes to a progressive reduction in muscle mass. Autophagic clearance of mitochondria through the process of mitophagy is required to remove impaired or damaged mitochondria, while mitophagy is a key regulator of muscle maintenance. Dysfunctional degradation of mitochondria is increasingly associated with aging (mitophaging), while mechanical stimuli have been shown to ameliorate the aging-induced impaired muscle mass and function; however, less is known about the potential effects of mechanical loading on mitophaging. The aim of the present study was to investigate the effect of mechanical stretching on mitophagy in aged myoblasts, in vitro. Methods: Cell senescence was replicated using a multiple cell division model of C2C12 myoblasts. The control and aged cells were cultured on elastic membranes and underwent passive stretching using a mechanical loading protocol of 15% elongation for 12 h at a frequency of 1 Hz. Cell signaling and gene expression responses of mitophagy-associated and myogenic regulatory factors (MRFs) were assessed through immunoblotting and qRT-PCR of the cell lysates derived from stretched and non-stretched control and aged myoblasts. Results: Mitophagy factor AMP-activated protein kinase (AMPK), mitochondrial biogenesis stimulator peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1a), and mitophagy/mitochondrial biogenesis factor Parkin were downregulated in control stretched myoblasts compared to non-stretched cells, while the specific mechanical loading protocol used also reduced the phosphorylation of unc-51-like autophagy-activating kinase 1 (p-ULK1) (p < 0.05), as well as the expression of myogenic factor 5 (Myf5) and myogenic factor 4 (myogenin) (p < 0.001). Interestingly, this mechanical loading resulted in increased PGC-1a and Parkin expression (p < 0.05) and induced the previously undetected BCL2 interacting protein 3-like (BNIP3L/NIX) and AMPK expression and p-ULK1 activation in the aged myoblasts. In addition, mechanical stretching differentially affected the expression of MRFs in aged cells, upregulating the early differentiation factor, Myf5 (p < 0.01), while downregulating the late differentiation factor myogenin (p < 0.001). Conclusions: These findings suggest the beneficial effects of mechanical loading on the impaired mitophagy and early differentiation in aged myoblasts, as indicated by the mitophagy initiation and the promotion of mitochondrial biogenesis in these cells. The mechanical loading-induced downregulation of mitophagy and myogenesis in the control myoblasts might indicate their loading-specific differential responses compared to the aged cells.

Despite the growing interest in brain structural plasticity and the substantial body of knowledge that has accumulated over recent decades, some issues remain poorly defined, leading to confusion in the interpretation of results. In addition to stem cell-driven neurogenesis in adult neurogenic niches (adult neurogenesis), neuronal precursors in a state of arrested maturation have also been described, representing a form of neurogenesis without division based on so-called "immature" or late-maturing neurons. These processes occur in different brain regions yet share certain molecular markers and temporal windows. Recent advances in comparative neuroplasticity have further complicated our understanding. Studies reveal a reduction in adult neurogenesis in the olfactory bulb and hippocampus of large-brained, gyrencephalic mammals compared with small-brained species such as rodents. Conversely, a higher prevalence of immature neurons has been reported in the neocortex and amygdala of larger-brained mammals. It is becoming evident that evolutionary trade-offs took place in distinct plastic processes, resulting in the predominance of certain forms in particular species, while others coexist and share overlapping markers. Regardless of the approach employed (neuroanatomical, immunocytochemical, phylogenetic, or transcriptional), current evidence indicates substantial heterogeneity in cell types with different origins and fates across diverse mammalian species. These patterns appear to be sculpted by evolutionary pressures yet unified by shared transient maturational states.

Skeletal muscle myogenesis is a crucial factor influencing meat production in livestock. MicroRNAs (miRNAs) play a significant role in skeletal muscle myogenesis. The objective of this study was to identify key miRNAs involved in the process of goat skeletal muscle satellite cell (MuSC) differentiation into myotubes. We performed miRNA expression profiling analysis during the proliferation phase (cultured in growth medium, GM) and the differentiation phase (cultured in differentiation medium for 1 day and 5 days, classified as DM1 and DM5, respectively) of goat skeletal muscle satellite cells (MuSCs). A total of 1846 miRNAs were identified in MuSC samples, of which 677 differentially expressed miRNAs (DEmiRNAs) were screened through pairwise comparisons across three groups (GM vs. DM1, GM vs. DM5, and DM1 vs. DM5), and the results were further confirmed by a quantitative real-time PCR assay. Time-series expression profiling facilitated the categorization of the DEmiRNAs into eight distinct clusters, one of which demonstrated a significantly downregulated expression pattern (p < 0.05). Functional enrichment analysis revealed that the target genes of DEmiRNAs are involved in several pathways that are critical for myogenesis, including Hippo, TGF-β, MAPK and cell adhesion molecules. Interaction network analysis identified 19 miRNAs and 56 mRNAs associated with muscle cell development. Notably, novel-m0047-5p emerged as a key regulator, exhibiting strong negative correlations (r = -0.88 to -0.89, q < 0.01) with muscle-related target genes FOSB, CPT1B, and MYOZ2. These findings elucidate miRNA-mediated regulatory networks in goat myogenesis and provide candidate molecular targets for genetic improvement of meat production traits.

The ontological categorization of the cellular elements of the brain was proposed over a century ago by Santiago Ramón y Cajal (neurons, astroglia) and Pío del Río-Hortega (oligodendroglia, microglia). It combines histochemical observations of morphology with allied inferences about the specialized functions and origins (ectoderm or mesoderm) of each cellular element. This ontology shapes modern neuroscience, with the main non-neuronal cells-astroglia, oligodendroglia and microglia-viewed as having distinct primary roles relating respectively to the metabolic support, myelination and immunoprotection of neurons, the information signaling cells. Yet contemporary techniques, ranging from electrophysiology to single-cell transcriptomics and ultrahigh resolution spectroscopy, are revealing intersecting molecular profiles and functional capacities of these cell groups, for example metabolic support, neuroimmune and signaling functions in oligodendroglia. Here we identify discrepancies in current glial paradigms, from empirical, evolutionary and pragmatic perspectives. We suggest a subset of small, iron-rich glial cells, usually with few processes, often viewed as oligodendroglia with myelin-related primary functions, instead have iron-related primary functions that are central to all aspects of brain activity. We call these 'ferriglia'. We discuss implications for pathogenesis across the spectrum of neuropsychiatric and neurological disorders, including neurodegenerative conditions such as Alzheimer's disease and other less common cognitive, movement and neurobehavioral disorders, stroke and cerebrovascular disease, glioblastoma and other brain cancers and neuroimmune conditions. We also briefly address the question of where ferriglia may reside within existing glial compartments and lineages, implications for the ontological classification of other glial cells, and research challenges that must be overcome going forward.

During aging, bone marrow stromal (a.k.a. mesenchymal stem) cells (BMSCs) shift their lineage commitment away from osteogenesis and towards adipogenesis, resulting in bone loss and marrow fat accumulation. We previously reported that during osteogenesis, BMSCs activate mitochondrial oxidative phosphorylation (OXPHOS) at least in part by downregulating cyclophilin D (CypD) expression and, consequently, mitochondrial permeability transition pore (MPTP) activity. We also reported that in contrast, during adipogenesis, BMSCs upregulate CypD and MPTP, activate glycolysis and inhibit OXPHOS. To further study the role of CypD in BMSC bioenergetics, adipogenesis and bone marrow fat accumulation, we used CypD loss-of-function (LOF) or gain-of-function (GOF) models in osteo-adipoprogenitors in vitro and in vivo. We found that CypD LOF and GOF are associated with impaired and enhanced BMSC adipogenesis, respectively, both in vitro and in ectopic bone grafts in vivo. In addition, bioenergetic profiling and metabolomic analyses show evidence of corresponding metabolic reprogramming in CypD LOF and GOF cells. In summary, our study demonstrates the role of CypD-regulated mitochondrial metabolism during BMSC adipogenesis, facilitating the understanding of stem cell fate determination and the molecular mechanism of age-related bone loss as well as bone marrow fat accumulation.

Mice genetically deficient in α-Klotho (henceforth Klotho) display accelerated aging. The mechanisms are only partially understood. Here, we examine how these relate to the 12 hallmarks of aging consisting of chronic inflammation (inflammaging), as well as damaging changes to the genome (DNA damage), telomeres, epigenetic regulation, proteostasis, nutrient sensing, mitochondria, stem cells, intercellular communication, macroautophagy, microbiome and cell replication (senescence). Inflammation aggravates the other hallmarks. We report that Klotho counters the majority of these hallmarks. It ameliorates mitochondrial function and reduces reactive oxygen species (ROS), telomere attrition and cellular senescence. It protects against inflammation by inhibiting NF-κB and the NLRP3 inflammasome. This applies to inflammaging, several chronic inflammatory diseases, atherosclerosis, diabetes, and Alzheimer's disease. Klotho also counters some aging factors outside of these hallmarks. Low Klotho (often due to kidney disease) produces hyperphosphatemia, which injures cells (especially endothelial cells) and promotes aging. Another key action of Klotho is the mitigation of fibrosis in major organs (kidneys, heart, lungs and other), mainly through the inhibition of TGF-β and Wnt. Klotho also protects against muscle atrophy (sarcopenia)-a common feature of aging-and exhibits anti-cancer activity. We describe several factors that increase Klotho, and are potentially amenable to clinical therapy.

Neural progenitor cell (NPC) transplantation is a promising strategy for spinal cord injury repair, as graft-derived neurons can integrate into host circuitry and promote functional recovery. While the brain-regional and dorsoventral identities of NPCs are known to influence graft composition and performance, the importance of axial (rostrocaudal) identity, specifically whether NPCs must be matched to the spinal level of injury, remains poorly understood. To address this, we compared outcomes following transplantation of NPCs isolated from the anterior embryonic spinal cord (A-NPCs) versus the posterior spinal cord (P-NPCs) in a mouse model of C5 cervical dorsal column injury. Following transplantation, NPCs retained their intrinsic molecular axial identities; P-NPC grafts maintained significantly higher expression of the lumbar-associated gene HoxC10 and possessed a higher proportion of Chx10-high V2a neurons compared to A-NPCs. Despite these maintained molecular differences, A-NPC and P-NPC grafts were indistinguishable in neuronal and glial density, axon outgrowth, and their ability to support host axon regeneration, including the corticospinal tract. Long-term behavioral testing and retrograde transsynaptic tracing revealed no significant differences between groups in the recovery of skilled pellet reaching, grip strength, or synaptic integration with host cervical motor circuitry. These findings demonstrate that although transplanted NPCs retain their molecular axial identity in the adult injured environment, this identity is not a primary determinant of anatomical integration or functional outcome. Our findings suggest a degree of plasticity in graft-host interactions and indicate that strict segment-matching is not essential for the efficacy of NPC-based therapies in spinal cord injury.

Genome editing has emerged as a transformative approach for understanding and treating retinal degenerative diseases. Combining this technology with pluripotent stem cells provides an ideal platform for modeling human development and disease, and investigating emerging therapeutic strategies ultimately aimed towards in vivo correction. This approach enables both functional studies to understand retinal degeneration and the early development of targeted therapies for inherited disease. This review offers a comprehensive overview of genome-editing techniques and the ability to create new clinically relevant models to understand human disease in retinal research, focusing on the use of the CRISPR-Cas9 system in induced pluripotent stem cells (iPSCs) and embryonic stem cells (ESCs), as well as highlighting recent advancements in base and prime editing. Gene editing in various retinal diseases is discussed in context of studies focusing on disease modeling or developing therapeutic strategies. Continued refinement of these techniques will be essential for advancing translational applications in retinal disease treatment.

Diabetes mellitus is a global healthcare issue of epidemic proportions. At the root of these disorders, characterized by poor glucose regulation and insulin deficiencies, is the pancreatic beta cell and insufficient insulin signal transduction in peripheral tissues. Residual c-peptide secretion and persisting beta cells have been found in patients who have been living with type 1 diabetes for over 50 years. Thus, beta cell regeneration has been vastly studied in rodents, and many agents to expand beta cell mass are under rigorous investigation for the treatment of diabetes. Multipotent stromal cells (MSC), isolated from human bone marrow, have an immunomodulatory and pro-regenerative secretome that can aid in repairing damaged tissues, including pancreatic islets. MSC transplantation has been shown to reduce hyperglycemia and orchestrate islet repair in experimental diabetes models and is currently being assessed in clinical trials. While the immunomodulatory mechanisms of MSC are well-studied, the beta-cell-regenerative mechanisms are unknown. MSC likely play a regenerative role by signaling to resident progenitor or precursor cells in the pancreas; however, the decades-long controversy surrounding the origin of regenerated adult beta cells remains unresolved. Herein, we take a deep dive into the role of MSC in the treatment of diabetes and the potential cellular mechanisms behind the MSC stimulation of beta cell regeneration.

Osteoarthritis (OA) is a multifactorial disease characterized by inflammation, extracellular matrix remodeling, and joint degeneration, and it still lacks disease-modifying treatments. Here, we applied an ex vivo OA model based on transwell co-cultures of cartilage and synovial membrane explants harvested from OA patients to compare the effects of adipose-derived stem/stromal cell (ASC) conditioned medium (CM) with dexamethasone (DEX), a clinically used corticosteroid. Explants were treated for 48 h with 100 nM DEX, CM derived from 5 × 105 ASCs, or left untreated. Outcomes included gene and protein expression of key mediators, metalloprotease and aggrecanase activities, and nitric oxide release. DEX significantly reduced inflammatory markers (e.g., PTGS, IL-1β, and IDO) and VEGF expression in both tissues, while CM did not elicit consistent anti-inflammatory effects. Regarding matrix remodeling, both treatments reduced metalloprotease activity, with DEX modulating MMP3 and MMP13 expression in both tissues and CM reducing only MMP3 expression in cartilage while presenting high levels of TIMP-1. These results confirm the robustness of the model, demonstrated by reproducible responses to DEX and its high-throughput potential, and underscore the need for mechanistic studies to optimize novel biotherapeutics.

The therapeutic potential of prodigiosin as a hydrophobic anticancer agent can be enhanced by various approaches, one of which is the loading of PG into extracellular vesicles. Drug distribution and stability in aqueous media play a crucial role in targeting and accumulation, thereby enabling the attainment of therapeutically effective drug concentrations. Extracellular vesicles are nano-sized, cell-derived vesicles with a lipid bilayer membrane. Extracellular vesicles can be utilized as drug carriers for both water-soluble and non-water-soluble therapeutic agents. We hypothesized that microvesicles could effectively address the current challenges of prodigiosin delivery. Several different techniques have been developed for fabricating extracellular vesicles. These include microvesicles induction by cytochalasin B treatment as well as cell cultivation in serum depleted media. In our study, prodigiosin, like cytochalasin B, demonstrated efficacy in microvesicles formation based on protein quantification and Nanoparticle Tracking Analysis. In addition, Nanoparticle Tracking Analysis showed that vesicles from mesenchymal stem cells are more stable under ultrasound exposure. Microvesicles encapsulating prodigiosin, compared to unmodified naïve ones, demonstrated slightly increased zeta potentials and hydrodynamic diameters, which probably contributed to better stability. We demonstrated that ultrasonic treatment for the loading of prodigiosin does not significantly increase the proportion of prodigiosin-positive microvesicles in comparison with microvesicles induced with prodigiosin; moreover, this method cannot be considered as optimal due to its disadvantages, such as particle aggregation. Prodigiosin-induced and prodigiosin-loaded microvesicles from mesenchymal stem cells were significantly smaller and less polydisperse in size. Overall, prodigiosin encapsulated in extracellular vesicles might be more suitable for medical and clinical applications compared to pure forms of PG due to their cell membrane compatibility.

Background: Chronic liver fibrosis is a progressive pathological condition characterized by excessive extracellular matrix deposition and architectural remodeling, which may ultimately lead to cirrhosis and liver failure. Although mesenchymal stem cells (MSCs) exhibit antifibrotic and immunomodulatory properties, their therapeutic effects in established chronic liver fibrosis remain incompletely defined. This study aimed to evaluate the biochemical, hematological, and histopathological effects of MSC therapy in a chronic thioacetamide-induced liver fibrosis model. Methods: A controlled preclinical experimental study was conducted using rats with liver fibrosis induced by intraperitoneal thioacetamide administration for 24 weeks. Animals were allocated into three groups: control, untreated fibrosis, and fibrosis treated with MSCs derived from human umbilical cord tissue after fibrosis establishment. Serum biochemical markers, hematological parameters, and liver histopathology were assessed. Fibrosis severity was evaluated using hematoxylin-eosin and Masson's trichrome staining and graded according to the METAVIR scoring system. Results: Thioacetamide exposure induced chronic liver injury characterized by marked elevations in serum transaminases, reduced albumin and total protein levels, hematological alterations, and early-to-intermediate fibrosis stages (METAVIR F1-F2). MSC-treated animals exhibited approximately 40-45% reductions in transaminase levels, partial recovery of hepatic synthetic function, and attenuation of hematological alterations. Histopathological analysis demonstrated a reduction in fibrotic burden and limitation of fibrogenic progression within METAVIR F1-F2 stages. Conclusions: MSC therapy partially mitigates biochemical, hematological, and histopathological alterations associated with chronic thioacetamide-induced liver fibrosis, supporting its potential as a modulatory strategy to attenuate fibrogenic progression and stabilize liver function rather than as a curative intervention.

Type 1 diabetes (T1D) is a T cell‑mediated autoimmune disorder characterized by the destruction of insulin‑producing β‑cells. Sialic acid‑binding Ig‑like lectin 15 (Siglec‑15) could inhibit T‑cell activation and suppress immune responses. However, the association between Siglec‑15 expression levels and T1D is largely unknown. Serum concentrations of soluble Siglec‑15 were quantified in a cohort comprising 34 individuals newly diagnosed with T1D and 21 healthy control subjects. A murine mesenchymal stem cell (MSC) line, C3H10 T1/2, was genetically engineered to stably express SIGLEC15 through lentiviral transduction. Non‑obese diabetic (NOD) mice were administered treatments with Siglec15‑expressing MSCs, control MSCs, or phosphate‑buffered saline. The present study evaluated diabetes incidence, blood glucose concentrations, the severity of insulitis and the composition of immune cell populations in the pancreatic lymph nodes and spleens. In the present study, measurement of human serum specimens by ELISA revealed a positive association between new‑onset T1D and soluble Siglec‑15 levels. In NOD mice, treatment with Siglec15‑MSCs resulted in a significant reduction in diabetes incidence, preservation of insulin‑positive islets and mitigation of insulitis. Flow cytometric analysis demonstrated an increase in CD4+effector memory T cells within the pancreatic‑draining lymph nodes of mice treated with Siglec15‑MSCs, while no significant alterations were observed in splenic T cell populations or the frequencies of regulatory T cells. The findings of this study underscore the potential of Siglec‑15‑overexpressing MSCs as a promising cell‑based therapeutic approach for T1D, primarily through the localized modulation of memory T cells within the pancreatic lymph nodes.