Anti-osteoporotic drugs are effective in reducing fracture risk, yet their long-term management is frequently associated with paradoxical skeletal complications, the cellular basis of which remains poorly defined. Bone remodeling is a continuous process that depends on functional coupling between osteoclast-mediated bone resorption and mesenchymal stem cell (MSC)-driven bone formation. Using a three-dimensional dynamic in vitro system that preserves osteoclast activity on bone surfaces, we investigated how anti-osteoporotic agents modulate osteoclast-MSC interactions. We found that zoledronic acid suppressed osteoclast maturation and resorptive activity, while concurrently inhibiting MSC migration and subsequent osteoblastic differentiation. In contrast, teriparatide enhanced MSC recruitment and osteogenic differentiation but also accelerated the maturation of multinucleated osteoclasts and bone resorption. These findings indicate that both anti-resorptive and anabolic therapies exert complex multicellular effects that extend beyond their classical lineage-specific actions, leading to altered coupling dynamics during bone remodeling. Our study provides cellular insight into drug-associated skeletal side effects and establishes a functional platform for evaluating the multicellular impact of osteoporosis therapies.

Pancreatic cancer often referred to as the "king of cancers," is a disease with no symptoms and lacks effective therapy. Current treatment options for pancreatic cancer have not been successful, highlighting the need for new therapeutic avenues with minimal side effects and improved effectiveness. In recent years, new cell-based therapies using stem cells or their derivatives have shown promise in treating various diseases, including cancer. Here, we aimed to explore the impact of the secretome of human amniotic mesenchymal stem cells (hAMSCs) on Panc1 pancreatic cancer cells, focusing on the insulin-like growth factor 1 receptor (IGF-1R)/FoxO signaling pathways. To achieve this, we developed a co-culture system utilizing 6-well plates transwell. After 72 h, cell death and cell invasion in hAMSCs-treated Panc1 cells were assessed using Western blot, Scratch assay, and DAPI staining. Our results showed an increase in the expression levels of AKT, AMPK, FasL, and cleaved caspases 3/9, while there was a decrease in FoxO, IGF-1R, PI3K, 14-3-3, p-FoxO, MMP3, Integrin α3, and Integrin β6 expression. These findings suggest that hAMSCs' secretome promotes cell death and inhibits cell invasion in Panc1 cells, indicating its potential as a novel targeted therapy approach for pancreatic cancer.

Primary osteoporosis is a major age-related disease with a significant global health burden. While iron accumulation is a known risk factor, the mechanisms linking it to bone loss remain unclear. Here, we report that impaired mitophagy in bone marrow mesenchymal stem cells (BMSCs) is a hallmark of osteoporosis and is critically exacerbated by iron accumulation. We found that iron accumulation in BMSCs inhibits mitophagy, leading to mitochondrial dysfunction, increased oxidative stress, and cellular senescence, ultimately impairing osteogenic differentiation. Importantly, targeted activation of mitophagy, either pharmacologically or genetically, restored mitochondrial health, reduced senescence, and rescued bone formation. Conversely, Pink1 deficiency in BMSCs was sufficient to induce osteoporosis. Mechanistically, we identified that the mitochondrial ferritin FTMT is upregulated under iron-loading conditions and binds to PINK1, suppressing its phosphorylation and thereby preventing mitophagy initiation. This pathway is clinically relevant, as BMSCs from osteoporotic patients with high ferritin levels showed elevated FTMT and reduced PINK1 phosphorylation. Therefore, we identify a novel pathway in which FTMT-mediated disruption of mitophagy drives iron-induced osteoporosis. Our findings highlight mitophagy activation as a therapeutic strategy to prevent and treat bone loss under iron accumulation.

Acute myeloid leukemia (AML) is an aggressive bone marrow disease, characterized by increased levels of bone morphogenetic proteins (BMPs). In this study, the impact of the BMP-enriched leukemia environment was determined on surrounding cells, notably mesenchymal stem cells (MSC). BMP-2, 4, 7, 9, and TGFβ1 were presented via a biomimetic extracellular matrix to healthy and AML-MSC. We have previously shown the existence of a bidirectional cross-talk between BMP receptors and integrins, which tightly connect cell adhesion to cell differentiation. In this study, we investigated how BMPRs and integrins are regulated in the AML microenvironment, in particular in the context of MSC adhesion and differentiation. Smad phosphorylation and cell adhesive responses were assessed for MSC cultured on biomimetic materials with matrix-bound BMPs/TGFβ1 using a recently-developed high-content immunofluorescence method. The specific role of BMP receptors and of integrin beta chains in the activation of pSmad signal, cell adhesion and cell spreading was studied using silencing RNA. 33% of the AML-MSCs exhibited increased receptor levels, with higher variability for BMPR2, β1 and β5 receptors. Notably, AML-MSC exhibited an upregulated and sustained pSmad signaling, associated to ALK5, ALK6 and BMPR2 dysfunctions. AML-MSC adhesion was strongly impaired, associated with a loss of cooperation between BMPR and β integrins. Unexpectedly, β integrins inhibited AML-MSC adhesion, while BMPRI receptors promoted it, notably ALK5. Furthermore, we proved that MSCs from AML patients exhibit an impaired differentiation into osteogenic, chondrogenic and adipogenic lineage. For the first time, we proved here that MSCs present in the AML microenvironment present an altered adhesion and differentiation, due to an altered cross-talk between BMPRs and integrins. This paves the way for future therapeutic strategies taking into account ALK5 and integrin beta chains in AML disease.

Driven by endogenous platelet-derived growth factor receptor α (PDGFRα)-positive cells, in-body tissue architecture (iBTA) enables the autonomous formation of vascularized tissues within subcutaneously implanted molds, overcoming the limitations of traditional cell therapies. The cellular mechanisms were investigated in PDGFRα reporter mice. Recruited PDGFRα-lineage cells were closely associated with Pecam-1-positive vessels and often adopted perivascular positions. Flow cytometry revealed that these cells expressed the mesenchymal stem/stromal cell (MSC) markers (CD73, CD90, and CD105). Additionally, the cultured isolates maintained MSC morphology and demonstrated osteogenic, chondrogenic, and adipogenic differentiation potential in vitro. The approach was successfully scaled to a porcine model, which exhibited organized tissue maturation, including vascular structures and collagen deposition, within 2 weeks. iBTA eliminates the need for cell isolation and immunosuppression by leveraging resident PDGFRα-positive MSCs for in situ tissue generation, providing a direct pathway for autologous vascular tissue engineering applications.

Inactivating NOTCH1 mutations in head and neck squamous cell carcinoma (HNSCC) were described over a decade ago, suggesting a tumorsuppressor function-unlike its oncogenic role in other tumors. Today, much debate persists regarding a putative oncogenic role in HNSCC as well, with reports that NOTCH1 signaling drives tumor growth and a cancerstemcell (CSC) phenotype. In this work, comprehensive experiments unequivocally demonstrate that NOTCH1 is a tumor suppressor in HNSCC regardless of mutation or activation status and that it reduces CSC frequency. We developed a signature of NOTCH1 activation showing the pathway is associated with very early differentiation, an altered tumor microenvironment, and better prognosis. Clarifying whether NOTCH1 occasionally functions as an oncogenic driver in HNSCC is crucial to prognosis and personalized therapy. The results presented unify the field, reconcile conflicting data, and provide critical insights into the biological and clinical significance of NOTCH1, with broader implications in other squamous carcinomas with NOTCH1 mutations.

Stem cell-derived extracellular vesicles (EVs) hold significant promise for tissue regeneration due to their potent therapeutic cargo. However, their clinical translation is hindered by rapid clearance from target sites following systemic or local administration, leading to inefficient delivery and limited therapeutic efficacy. To overcome this critical challenge, we developed a click-crosslinked dopamine-functionalized hyaluronic acid hydrogel system (Dopa-HA) for the sustained and localized delivery of EVs. Dopamine was chemically conjugated to the click-crosslinked hydrogel to enhance the robust immobilization of EVs. The physicochemical properties of this hydrogel system were subsequently characterized, including dopamine functionalization degree, rheological behavior, degradation rates, and in vitro protein release profiles. Our investigations revealed that Dopa-HAs (4% and 14%) enable controlled release of model proteins (albumin and cholesterol), with release kinetics directly tunable through adjustments in the degree of dopamine functionalization. Particularly, when loaded with osteogenic stem cell-derived EVs, the Dopa-HA significantly accelerated the osteogenic differentiation of encapsulated stem cells in vitro. In vivo study in a rat calvarial defect model demonstrated that Dopa-HA markedly enhanced bone regeneration, with Dopa-HA-EV constructs achieving nearly twofold faster defect filling than HA-EV controls. Biodistribution analysis of fluorescently labeled EVs further revealed prolonged local retention at the defect site for up to 10 days post-implantation. This dopamine-functionalized hydrogel platform represents a significant advancement, effectively addressing the challenge of EV delivery by extending their local availability and thereby augmenting therapeutic outcomes.

Alzheimer's Disease (AD) is a central nervous system (CNS) neurodegenerative disease leading to dementia, but can also show symptoms of motor deficits. It is not clear whether the peripheral motor deficits in AD are derived from upstream centers or intrinsic to the neuromuscular circuit. This study developed a model to evaluate the neuromuscular pathology of familial AD (fAD) in a functional neuromuscular junction (NMJ) system.

Not available.

Genetic variants in components or regulators of the RAS-MAPK signaling pathway are causative for severe and early-onset hypertrophic cardiomyopathy (HCM) in patients with Noonan syndrome (NS). Despite paracrine communication being considered to play a pivotal role in the etiology of cardiomyopathies, there is a paucity of knowledge about the underlying pathomechanism that leads to the development of hypertrophic cardiomyopathy and cardiac fibrosis in NS.

The olfactory mucosa has emerged as a promising source of mesenchymal stem cells with neurogenic potential. These cells exhibit neural, glial, and mesenchymal properties, making them attractive candidates for regenerative medicine, particularly in treating neurodegenerative and immunemediated disorders.

Plasma medicine has emerged as a rapidly emerging interdisciplinary area of research that investigates the interaction of cold atmospheric plasma (CAP) with biological systems. The therapeutic power of CAP relies on the controlled generation of reactive oxygen and nitrogen species (RONS), pulsed electric fields, and ultraviolet radiation, which synergistically enable specific bioactivity. This review summarizes CAP research from the past decade, including in vitro, in vivo, and clinical studies across biomedical applications, and categorizes CAP sources by their distinctive physicochemical properties and associated medical relevance. The discussion highlights that treatment efficacy in wound healing, cancer therapy, and antimicrobial applications is strongly device-dependent, underscoring the critical role of plasma source design in clinical outcomes. CAP demonstrates significant antimicrobial effects, reduces microbial load, and preserves the integrity of healthy tissue. It promotes hemostasis and accelerates wound healing through vascularization, cell proliferation, and microcirculation. In oncology, CAP exhibits selective antitumor effects, including skin cancers and other vertebrate tumor models. Its applications in dentistry reflect its versatility in disinfection and in aiding implantation. Furthermore, CAP can stimulate the growth of stem and cultured cells via nitric oxide-mediated mechanisms. Recent studies have highlighted the potential of CAP in surface modification and transdermal drug delivery. Furthermore, plasma-activated media and solutions have garnered significant interest due to their diverse applications in plasma medicine. The review provides a comprehensive overview of all available literature, facilitating biomedical scientists in their further translational research in this field.

Multiple myeloma (MM) is a virtually incurable plasma cell malignancy characterized by malignant cells that expand within the tumor-permissive bone marrow (BM) microenvironment. Novel strategies are urgently needed to improve the outcomes of patients with difficult-to-treat and therapy-refractory disease. The ability to genetically manipulate T-cells and the introduction of adoptive cellular therapies (ACTs) has improved the treatment of relapsed and/or refractory (RR)MM. Emerging evidence supports the efficacy of ACTs as early lines of cancer treatment, potentially even as an alternative to autologous hematopoietic stem cell transplantation. Chimeric antigen receptor (CAR) T-cell therapies based upon genetically engineered patient-derived T-cells are utilized in routine clinical practice, however severe toxicities, therapeutic resistance, exorbitant costs, a cumbersome manufacturing process and production logistics limits their broader application. Tumor-infiltrating lymphocytes (TILs) can also mediate tumor regression and lead to durable responses, but wider efficacy is restricted by limited accessibility, reduced proliferative capacity and low effector function. In this context, autologous T-cells engineered to express T-cell receptors (TCRs) represent an intriguing option to improve MM treatment. Immunoproteasomes represent an essential cornerstone of adaptive immunity and are required for the efficient processing of antigenic peptides presented by MHC class I (MHC-I) molecules to cytotoxic CD8+ T-lymphocytes (CTLs). Recent studies have demonstrated that immunoproteasome activation increases the presentation of tumor-specific neo-antigens, thereby offering a potential strategy to improve the antimyeloma effects of T-cell-mediated immunotherapies. Here, we discuss advantages and strategies that support the administration of TCR-engineered T-cells for the treatment of MM. This review focuses on the role of immunoproteasome dependent antigen processing in shaping the myeloma immunopeptidome and enabling TCR-based immunotherapy. We discuss how modulation of neoantigen presentation may inform the design of TCR-engineered T cells and related immunotherapeutic strategies for MM.

MAGEB16 (Melanoma-associated antigen B16) is an X-linked cancer-testis antigen belonging to the MAGE-B family, whose expression is tightly regulated by a promoter DNA-methylation switch that restricts transcription primarily to the male germ line under normal physiological conditions. In addition to its established roles in spermatogenesis and oncogenesis, emerging functional, epigenomic, and genetic evidence points to MAGEB16 as an epigenetically sensitive modifier of early developmental programs implicated in neurodevelopmental disorders such as Autism Spectrum Disorder (ASD). In this study, we performed an integrative analysis combining MAGEB16's chromosomal context, molecular interaction networks, and methylation-dependent regulatory features, alongside experimental depletion datasets from pluripotent stem cells, perinatal cord-blood methylome data from ASD cohorts, peripheral transcriptomics linked to neuropsychiatric risk and recently reported genetic variant associations. Our synthesis identifies underlying evidence indicating that MAGEB16 participates in epigenetically regulated lineage specification processes during early embryonic development. We propose a unified model in which MAGEB16 acts as a dosage- and timing-dependent regulator of early lineage commitment. Disruption of its epigenetic control, particularly during X-chromosome-enriched developmental periods, may influence neurodevelopmental pathways toward ASD-associated phenotypes. These findings position MAGEB16 as a candidate epigenetic-susceptibility factor linking germline-restricted regulatory changes, that could influence early brain development and increase the risk for neurodevelopmental conditions. See also the graphical abstract(Fig. 1).

[This corrects the article on p. 1064 in vol. 19, PMID: 33013264.].

Adult T-cell leukemia/lymphoma (ATLL) is a rare and aggressive malignancy of mature T-cells caused by chronic infection with Human T-cell Leukemia Virus Type 1 (HTLV-1). Despite advances in understanding its pathobiology, ATLL remains associated with poor clinical outcomes, largely due to intrinsic chemoresistance and immune evasion mechanisms driven by viral oncogenes and acquired genetic alterations. The discovery of frequent mutations in TCR/NF-κB, JAK/STAT, and apoptotic pathways has unveiled novel therapeutic vulnerabilities, while agents such as mogamulizumab have demonstrated clinical efficacy in relapsed settings. Antiviral therapies and allogeneic hematopoietic stem cell transplantation (allo-HSCT) represent pillars of treatment for selected patients, but durable remissions remain rare. This review comprehensively summarizes the molecular underpinnings of ATLL, highlights the evolving therapeutic landscape, and discusses emerging research directions aimed at improving patient outcomes.

Tissue engineering is an efficient method for constructing functional skin equivalents to treat large-area skin wounds. However, the source of seed cells is limited.

Relapse after allogeneic hematopoietic stem cell transplantation (HSCT) remains a major clinical challenge in higher-risk myelodysplastic neoplasms (MDS). Although hypomethylating agents have been evaluated as posttransplant maintenance therapy, their efficacy remains uncertain.

Autoimmune and immune-mediated alopecias demonstrate how a site-specific failure of immune privilege can produce reversible or irreversible hair loss. In alopecia areata (AA), cytotoxic injury is concentrated at the anagen bulb but preserves the stem cell pool, permitting regrowth following immune suppression. Lichen planopilaris (LPP) and frontal fibrosing alopecia (FFA) feature a spectrum of chronic interface dermatitis that destroys the stem cell niche, leading to permanent fibrosis. These entities overlap in bulge-targeted inflammation and histopathology but diverge in clinical distribution and demographic risk. Discoid lupus erythematosus (DLE) of the scalp reflects immune-complex-driven complement injury to the upper follicle, whereas central centrifugal cicatricial alopecia (CCCA) represents a fibroblast-dominant process associated with chronic stress and is sustained by stromal remodeling. Here, we frame these entities as four follicular immune network archetypes defined by the axial locus of immune privilege collapse, effector programs, loss of tolerogenic programs, stromal trajectories, and dermoscopic correlates. Using a Network Engineering for Site-Specific Tolerance (NEST) framework, we situate these archetypes within a three-tier taxonomy comprising intrinsic follicular privilege, local tolerogenic repertoires, and stromal checkpoint circuits. Specifically, AA localizes to the anagen bulb, DLE spans the upper follicle and interfollicular epidermis, LPP/FFA targets the bulge stem cell niche, and CCCA converges on the upper follicle-interfollicular epidermis unit. Within their respective niches, AA and DLE exhibit comparatively resolved clonotypic effector modules dominated by pathogenic T cells or B cells, whereas LPP/FFA and CCCA are framed as polyclonal networks in which the failure of tolerogenic programs or stress signaling pathways constitutes the dominant archetypal engine.