Search Results (1,636)

Background: Treatment-resistant obsessive–compulsive disorder (OCD) is a heterogeneous and clinically challenging condition. Growing evidence suggests alterations in glutamatergic signaling within cortico–striatal–thalamo–cortical circuits, including those involving medium spiny neurons (MSNs), as well as genetic factors affecting synaptic organization, although the biological mechanisms underlying differential treatment response remain incompletely understood. Methods: This multicenter study presents a translational research framework aimed at investigating potential molecular and cellular correlates of treatment response in a cohort of patients with OCD, stratified according to their response to pharmacological treatments and transcranial magnetic stimulation (TMS). Peripheral blood mononuclear cells from clinically defined subgroups are reprogrammed into human induced pluripotent stem cells and differentiated into MSN-enriched neuronal cultures, enabling in vitro investigation of morphological, biochemical, and transcriptomic features associated with different clinical profiles. Optogenetic and pharmacological stimulation paradigms are applied to probe selected aspects of neuronal activation in vitro, providing a controlled and simplified experimental framework to explore cellular responses under different treatment conditions. By integrating clinical phenotyping with patient-derived cellular models, this study establishes a translational platform for hypothesis generation in the investigation of treatment response in OCD. Results and Conclusions: Preliminary clinical observations from an initial cohort undergoing neuromodulation are also reported to document feasibility and early clinical implementation of the study, providing an initial characterization of the cohort. Full article

Glioblastoma multiforme (GBM) remains the most aggressive and therapeutically intractable primary brain tumor, with many patients experiencing rapid relapse despite maximal surgical resection followed by standard chemoradiation. This persistent failure reflects the convergence of profound tumor-intrinsic genetic heterogeneity and a highly dynamic, spatially structured, and immunosuppressive tumor microenvironment (TME). Together, these forces create strong selective pressures that fuel tumor evolution, intratumoral diversity, phenotype plasticity, diffuse invasion, and robust resistance to therapy. The TME of GBM is orchestrated through a complex interplay between diverse cellular constituents, including tumor-associated macrophages, reactive astrocytes, endothelial cells, pericytes, and GBM stem cells, and non-cellular components such as extracellular matrix remodeling, hypoxia, metabolic and nutrient gradients, and spatially patterned cytokine and chemokine signaling networks. Additionally, heterogeneity in blood–brain barrier (BBB) and blood–tumor barrier (BTB) complicates drug delivery and immune surveillance, reinforcing therapeutic resistance and regional tumor adaptation. Conventional two-dimensional cell cultures and animal models fail to sufficiently capture these multiscale, patient-specific interactions, limiting their translational predictive power. In this narrative review, we synthesize recent advances in GBM organoid technologies as physiologically relevant, three-dimensional platforms that more faithfully recapitulate TME for driving tumor evolution and treatment resistance. We compare complementary organoid strategies, including patient-derived GBM organoids that preserve native cytoarchitecture, cerebral organoid co-culture systems that reconstruct tumor–brain interactions, and advanced platforms incorporating immune and vascular features such as air–liquid interface cultures, microglia-enriched systems, and BBB/BTB-integrated models. Finally, we highlight emerging innovations such as spatial transcriptomics, organoid-on-a-chip systems, live imaging coupled with lineage tracing, genome engineering, and artificial intelligence integration that collectively position GBM organoids at the forefront of precision neuro-oncology, reproducing TME, enabling dynamic mapping of tumor evolution, and accelerating patient-specific therapeutic discovery. Full article

Neuromuscular and neurodegenerative (NMND) disorders are diseases that cause progressive damage to the central nervous system leaving patients with symptoms that negatively affect everyday living with death almost inevitable. These include amyotrophic lateral sclerosis (ALS), Lewy body dementia (LBD), and Parkinson’s disease (PD) with cases expected to increase in the future. Intranasally administered stem cell-derived exosomes/secretome have been seen as potential therapeutic options for these disorders in preclinical animal models. This study sought to observe the efficacy of mesenchymal stem cell-derived exosomes/secretome in patients with ALS, LBD, and PD. Based off these preclinical studies, we conducted a case-controlled series experiment with 86 patients with ALS, LBD, or PD, with the independent variable being the treatment and the dependent variable being the clinical response. These patients were recruited and given intranasal instillations of various MSC-derived exosome/secretome products. Subsequent treatments were given to patients who did not have a response to one product. Patients were followed up at one week, one, two, three, and six months post-treatment. Historical external controls were used for comparison to clinical outcomes. There were no serious adverse events in any patient. A total of 67 of 86 (77%) patients showed a positive clinical response to at least one product. Outcomes were strongly associated with greater treatment frequency for ALS and LBD. Intranasal administration of MSC-derived exosome/secretome products were safe, and most patients showed overall improvement with at least one product. Some patients also saw a substantial decrease in the rate of decline compared to historical controls. These results also give rise to the hypothesis: do MSC-derived exosomes/secretome treatments show efficacy in other NMND disorders? The primary limitation of this study is the 6-month follow-up. Full article

Diabetes mellitus is a chronic and progressive metabolic disorder associated with abnormal blood glucose levels. The term involves several diseases with different pathophysiology mechanisms and treatment strategies. Stem cell-based treatments represent an emerging strategy for patients with diabetes mellitus with severe pancreatic insufficiency and poor glycemic control. Over the last 20 years, researchers have investigated mesenchymal stem cell infusion and the transplantation of stem cell-derived β cells and islet tissues. This review aims to comprehensively discuss the latest advances in the field of stem cell use in diabetes, including clinical studies and preclinical experiments aiming at improving the efficacy and safety of stem cell use. Full article

Annually, there are more than two million deaths from liver disease. This is driven by organ inflammation and scarring, leading to a decline in function and regeneration. Frequently, this can develop into decompensated liver disease, resulting in the loss of physiological balance and toxin build-up within the body, with an increased risk of patient mortality. Currently, there are no approved medicines for the long-term treatment of liver cirrhosis. The only successful treatment option for end-stage liver disease patients is donor organ transplantation. However, patient requirement outstrips the number of donated organs. To address this bottleneck, researchers around the world have developed cell-based prototype systems to restore failing liver function, with some in clinical trials. Although significant progress has been made, no mainstream commercial liver assist products are available for routine clinical use. In this study we developed a stem cell-derived vascularized liver tissue implant prototype from pluripotent cells. The liver tissue was produced from a stem cell line that is banked at clinical grade, and displayed stable and mature liver function over a 6-week period in vitro. This included decreasing levels of the fetal marker, alpha-fetoprotein, when the serum albumin increased. This was further supported by stable alpha-1-antitrypsin secretion and cytochrome P450 function. Following the establishment of stable liver tissue, it was delivered as a cell product or attached to an electrospun polycaprolactone scaffold, to form a tissue implant. Next, cellular material was quality-controlled, and subsequently shipped to a contract research organization for external in vivo validation. The transplanted liver tissue functioned when implanted into the kidney capsule and subcutaneously, remaining functional for up to two weeks in vivo. Full article

Severe mental disorders, including schizophrenia (SCZ), bipolar disorder (BD), and major depressive disorder (MDD), are leading causes of global disability, yet current treatments remain largely symptomatic and fail to alter disease trajectories. Converging evidence from genetics, longitudinal studies, and systems neuroscience supports a dimensional and transdiagnostic architecture of psychopathology, involving shared polygenic risk and overlapping neurodevelopmental and circuit-level alterations. Traditional approaches—such as post-mortem brain analysis, neuroimaging, and animal models—have delineated core molecular perturbations (e.g., dopaminergic, glutamatergic, and GABAergic dysfunction), as well as informed translational frameworks for mechanistic investigation, but remain constrained by restricted access to dynamic processes and incomplete recapitulation of human-specific biology. The advent of human-derived cellular models, particularly human embryonic stem cells (hESCs) and induced pluripotent stem cells (iPSCs), has partially addressed these limitations, enabling the study of patient-specific neurodevelopment and synaptic function in vitro. Within this evolving landscape, the olfactory neuroepithelium (ONE) has emerged as an accessible source of neural progenitors, obtainable through minimally invasive procedures, providing a window into living human neurobiology. ONE-derived cells retain donor-specific genetic and epigenetic signatures while recapitulating disease-relevant phenotypes across major psychiatric disorders, including altered neurodevelopmental dynamics, synaptic gene expression, and inflammatory profiles. Here, we present a narrative review of the principal cellular and tissue models used in biological psychiatry, examining their respective strengths, limitations, and translational relevance across experimental contexts. By situating these approaches within a unified framework, we aim to clarify their complementarity, identify current gaps, and outline future directions, highlighting the emerging potential of ONE-based models to bridge genetic risk, cellular dysfunction, and clinical phenotype, thereby advancing precision psychiatry. Full article

Primary biliary cholangitis (PBC) is an autoimmune-mediated cholestatic liver disease characterized by the progressive destruction of intrahepatic bile ducts, which ultimately leads to hepatic fibrosis and cirrhosis. The current first-line therapy, ursodeoxycholic acid, is associated with a high rate of non-response. Moreover, second-line treatments are constrained by variable efficacy and safety concerns. Mesenchymal stem cells (MSCs), owing to their potent immunomodulatory and tissue-repairing capabilities, represent a promising new therapeutic strategy for PBC patients with poor response to conventional therapies. This review systematically outlines the pathogenesis of PBC, focusing on factors including genetics, environment, and immune dysregulation. Furthermore, it examines recent evidence on the mechanisms by which MSCs and their derivatives, such as exosomes, may intervene in PBC progression through immunomodulation, anti-fibrotic effects, and potential hepatic differentiation. This paper also reviews the current status and challenges of the clinical translation of MSCs therapy, and proposes that engineered modification and standardized preparation are the key directions to promote its application. In conclusion, this review provides a theoretical foundation and future directions for deepening the understanding of PBC pathogenesis and developing novel MSC-based therapeutic strategies. Full article

Soft tissue sarcomas (STS) comprise a rare and highly heterogeneous group of mesenchymal-derived malignancies, accounting for less than 1% of all cancers and characterized by diverse histologic and molecular subtypes. Despite their low incidence, STS account for a disproportionate burden of cancer-related morbidity and mortality, largely driven by their risk of metastatic dissemination. Early detection of metastatic spread is a cornerstone of preoperative staging, treatment planning, and postoperative monitoring in patients with STS. Although conventional imaging modalities remain fundamental for surveillance of metastatic disease, they may fail to accurately detect metastatic sites and provide limited insight into tumor biology. Advances in precision medicine have positioned liquid biopsy as a minimally invasive approach for the analysis of tumor-derived material, facilitating characterization of tumor biology and identification of prognostic biomarkers. Circulating tumor cells (CTCs) represent intact and viable tumor cells that provide unique genomic and phenotypic traits that could not be assessed using acellular tumor-derived material. They have emerged as promising biomarkers for monitoring disease progression, assessing treatment response, and stratifying prognosis. Particularly, their clinical value as prognostic biomarkers has been established in epithelial-derived malignancies. Despite these advances, the role of CTCs in STS remains largely investigational, mainly due to STS heterogeneity and the lack of standardized protocols for detection across platforms. Therefore, this narrative review summarizes the biomolecular mechanisms underlying CTCs in STS, including the role of phenotypic plasticity in tumor intravasation, anoikis resistance and its interaction with the tumor microenvironment, and stem cell-like phenotypes in tumor initiation at distant sites. Furthermore, we discuss current methodologies for CTC detection, highlighting emerging approaches developed to address the limitations of conventional methods. Finally, we provide a critical overview of subtype-specific detection strategies, as well as their clinical implications in treatment response monitoring and prognostic assessment. Full article

Inherited retinal dystrophies (IRDs) comprise a diverse group of genetic disorders that frequently result in irreversible vision loss due to photoreceptor dysfunction or degeneration. Among them, retinitis pigmentosa (RP) and achromatopsia (ACHM) are, in some cases, associated with pathogenic variants in PDE6A and PDE6C, respectively, which are key components of the phototransduction cascade. As most of IRDs still lack effective therapies, retinal organoids (ROs) provide a valuable in vitro model for the investigation of disease-associated mechanisms. Here, we generated induced pluripotent stem cell (iPSC)-derived ROs from an RP patient carrying compound heterozygous PDE6A mutations and from a patient with ACHM harboring a homozygous PDE6C mutation, along with their corresponding CRISPR/Cas9-corrected isogenic controls, which, to our knowledge, represent the first patient-derived RO models reported for the PDE6A and PDE6C genes. The mutant PDE6A line exhibited impaired neuroretinal vesicle formation and RO differentiation; however, a subset of RP-derived ROs matured appropriately and retained photoreceptor features. Moreover, the specific isoform expression pattern detected in retinal tissues reflected differences across developmental maturation stages that could influence disease severity. In contrast, the PDE6C_mutant ROs displayed normal structure and maturation, although cGMP hydrolysis within photoreceptors was likely compromised. In both models, CRISPR/Cas9-mediated correction restored the disease-associated phenotype resembling wild-type ROs. Collectively, these findings provide new insights into PDE6-associated pathogenesis, underscore the utility of patient-specific and gene-corrected ROs for elucidating IRD mechanisms, and support gene editing as a promising therapeutic strategy. Full article

Sepsis remains a leading cause of mortality worldwide and is increasingly recognized as a syndrome of dynamic immune dysregulation rather than a uniform inflammatory condition. The traditional paradigm of sequential hyperinflammation followed by immunosuppression has been replaced by a more complex view in which these processes coexist and evolve over time, contributing to marked interindividual variability in clinical outcomes. Despite advances in supportive care, current diagnostic and therapeutic approaches are still largely non-specific and fail to account for this biological heterogeneity. Extracellular vesicles (EVs) have emerged as key mediators of intercellular communication and potential integrators of immune activity in sepsis. These nanosized particles carry proteins, nucleic acids, lipids, and metabolites that reflect the functional state of their cells of origin and actively participate in immune regulation. Experimental and clinical evidence indicate that EVs exert context-dependent effects, contributing both to the propagation of inflammatory processes and the establishment of immunosuppressive states through the transfer of regulatory signals. Beyond their mechanistic role, EVs represent a promising platform for immune monitoring. Their cell-specific and dynamic molecular signatures have been associated with disease severity, organ dysfunction, and clinical trajectories, suggesting their role as biomarkers for patient stratification. In parallel, engineered and stem cell-derived EVs are being explored as therapeutic vectors capable of modulating immune responses and restoring immune homeostasis. In this review, we examine current concepts of immune dysregulation in sepsis and discuss how EVs may serve as both mediators and decoders of immune heterogeneity. We propose that EV-based approaches could bridge the gap between high-dimensional immunological profiling and precision immunotherapy, enabling more adaptive and individualized management of septic patients. Full article

Osteoporosis is an age-related metabolic bone disorder characterized by an imbalance between bone resorption and formation. Natural polyphenols have gained attention as potential complementary strategies for its prevention. In this study, we investigated the effects of a sustainable, polyphenol-rich extract from red grape pomace (GPE) on human mesenchymal stem cell (MSC) fate and its underlying mechanisms of action. We found that GPE significantly promoted osteogenic differentiation while suppressing adipogenic differentiation in canonical bone marrow-derived MSCs (BMSCs). This biological effect was preserved in adipose tissue-derived MSCs (AdMSCs) obtained from elderly patients (>65 years) at high cardiovascular risk. Mechanistically, GPE downregulated adipogenic markers (PPARγ, CD36 and FABP4) and enhanced osteogenic markers (RUNX2, ALP, OSX, BMP-2, OPN, COL1A1 and OCN). Moreover, GPE activated NRF2-dependent redox signaling, as evidenced by increased NRF2 nuclear translocation and transcriptional activity. Accordingly, GPE treatment significantly upregulated, or consistently increased, the expression of multiple NRF2 target genes, including HO-1, GPX, CAT, GCLC, and NQO1. Importantly, pharmacological inhibition of NRF2 attenuated GPE-induced ALP activity, confirming NRF2 as a key mediator of its osteogenic effects. Overall, grape pomace-derived polyphenols act as upstream modulators of redox-sensitive and osteogenic transcription factors, rebalancing MSC differentiation toward osteogenesis and mitigating age-related bone fragility. Full article

Hydrogel-based stem cell therapy uses different stem cells and bioactive molecules for wound healing in the treatment of diabetes and chronic burn wounds by accelerating angiogenesis, collagen deposition, and inhibition of inflammatory responses. Artificial vessels have already been used for patients with cardiovascular diseases, but most of them are polymeric, which can cause thrombosis and restenosis. 3D bioprinting combines cells, growth factors, and biomaterials to create a setting in which cells grow and differentiate into native tissue-like structures. The current study aimed to create a model of blood vessels using collagen and hyaluronic acid hydrogel combined with endothelial and muscle progenitor cells derived from amniotic mesenchymal stem cells using 3D bioprinting. A computer-aided design (CAD) software was employed to create the 3D models of a blood vessel model and printed using a 3D bioprinter with two printheads: one with bioink encapsulating endothelial progenitor cells and the second with bioink encapsulating smooth muscle progenitor cells. The blood vessel constructs were characterized morphologically and structurally by Fourier Transform Infrared (FTIR) Spectroscopy, thermogravimetric analysis (TGA), Scanning Electron Microscopy (SEM), immunohistochemistry, water uptake, and enzymatic degradation. Viability, proliferation, oxidative stress, vascular endothelial growth factor (VEGF) and nitric oxide (NO) production were assessed to demonstrate the cytocompatibility of the blood vessel constructs. Our results showed that collagen–hyaluronic acid hydrogels embedded with stem cells can be used for vascular constructs, meeting the desired requirements of biocompatibility and accuracy in reproducing the model created in the CAD software v1.0. Full article

Tendon injuries are common and debilitating musculoskeletal conditions that impose pain and debilitation to patients, significant challenges to medical professionals, and financial burdens to the healthcare system. Due to limited natural healing capacity, tendons typically undergo scar-mediated repair that compromises biomechanical integrity and increases the risk of reinjury. Despite a variety of therapeutic strategies, functional tendon healing remains a major clinical challenge. Mesenchymal stem cells (MSCs) represent an attractive strategy to improve tendon healing, largely due to their immunomodulatory and regenerative properties. Increasing evidence suggests that the therapeutic potential of MSCs is primarily attributed to their paracrine activity via the release of the secretome, a set of bioactive molecules that are known to mimic the immunomodulatory and regenerative properties of their parental cells. More recently, acellular approaches using MSC secretome derivatives, such as conditioned media and extracellular vesicles, have been largely explored for tendon healing. This review of the literature explores the therapeutic potential of MSC secretome derivatives for tendon healing, highlighting their advantages over cell-based therapies, proposed mechanisms of action, manufacturing and scalability considerations, and current state of research. Full article

Hematologic malignancies arise and progress within a systemic ecosystem in which the gut microbiota is an increasingly recognized, partially modifiable component. Across acute leukemias, chronic lymphocytic leukemia, plasma cell disorders, lymphomas, and clonal myeloid neoplasms, human studies consistently report reduced microbial diversity, depletion of barrier-supportive, short-chain fatty acid-producing commensals, and enrichment of Gram-negative, pro-inflammatory, or hospital-adapted taxa. These alterations are associated with pre-leukemic clonal expansion, adverse genetic and immunological features, progression from precursor conditions, and inferior outcomes after chemotherapy, immunochemotherapy, chimeric antigen receptor T-cell therapy, and allogeneic hematopoietic stem cell transplantation. Mechanistic work in animal models and ex vivo systems demonstrates that microbiota-derived signals and metabolites—including Th17/IL-17-skewing consortia and the lipopolysaccharide intermediate ADP heptose sensed by the cytosolic receptor ALPK1—can actively modulate hematopoietic stem and progenitor cell fitness, inflammatory circuits, and malignant cell survival, supporting a causal role in disease biology. At the same time, major knowledge gaps remain because most human cohorts are small, single-center, and cross-sectional, frequently rely on 16S rRNA profiling, and are vulnerable to dietary, geographic, and treatment-related confounding. Within this context, three translational domains appear particularly promising: pharmaco-microbiomics, microbiome-informed risk stratification, and rational microbiota-targeted interventions, particularly diet-based strategies and antimicrobial stewardship. Here, we provide an integrated, disease-spanning synthesis of these data, emphasizing clonal hematopoiesis and myeloid neoplasms as emerging examples of microbiota–marrow crosstalk and outlining practical priorities for embedding microbiome science into future hematologic trials. Routine microbiome profiling or empiric microbiota-directed therapies cannot yet be recommended in everyday hematology practice, but integrating microbiome science into prospective therapeutic and transplant trials offers a realistic path to improved disease modeling, biomarker development, and rational adjunctive strategies to enhance outcomes for patients with hematologic malignancies. Full article

Craniofacial and corneal neuropathic pain are disabling conditions characterized by persistent pain that is frequently refractory to conventional pharmacologic and interventional therapies. These disorders arise from complex interactions between peripheral nerve injury, neuroinflammation, and maladaptive central sensitization within trigeminal pathways, features that span neuropathic and nociplastic pain mechanisms as defined by the International Association for the Study of Pain, thus emphasizing the need for mechanism-based, patient-stratified treatment strategies. Regenerative medicine offers a paradigm shift from symptom suppression toward structural nerve repair and functional restoration. This narrative review examines the pathophysiological mechanisms underlying craniofacial and corneal neuropathic pain and critically evaluates emerging regenerative therapies, including autologous biologics (autologous serum tears and platelet-rich plasma), mesenchymal stem cells and their derivatives, exosomes and extracellular vesicles, and neurotrophic peptides. Particular emphasis is placed on corneal neuropathic pain as a translational model, given the cornea’s dense sensory innervation and the ability to non-invasively quantify nerve regeneration using in vivo confocal microscopy as an objective biomarker of treatment response. Clinical evidence across regenerative modalities varies by indication: cenegermin has demonstrated robust efficacy and regulatory approval for neurotrophic keratitis, while platelet-rich plasma shows growing evidence in temporomandibular disorders, myofascial pain, and occipital neuralgia. Cell-based and cell-free therapies demonstrate strong preclinical promise but remain limited by heterogeneous protocols and a paucity of large-scale randomized trials. Key barriers to translation include regulatory uncertainty, lack of standardized outcome measures, and workforce and implementation challenges. Advancing regenerative therapies for craniofacial and corneal neuropathic pain will require rigorous clinical trials, biomarker-driven patient selection, and multidisciplinary collaboration. Sex as a biological variable remains underexplored across all regenerative modalities and represents a priority for future research. Full article