PIEZO1 are mechanically-activated ion channels expressed in many cell types. Their pharmacological activation by the selective agonist Yoda1 has been reported to favor skeletal muscle regeneration by controlling the fate of myogenic precursors cells, but the underlying mechanisms remain largely unknown. Hereby, we investigated the possibility that PIEZO1 could control the release of small extracellular vesicles in myogenic C2C12 cells. Myoblasts and differentiated myotubes were treated with the PIEZO1 agonist Yoda1 (5 μM) for 24 hours. Released small extracellular vesicles were isolated by ultracentrifugation methods, and characterized by Western blotting, Nano Tracking and proteomic analysis. Pharmacological activation of PIEZO1 showed cell-type-specific effects: In myoblasts, Yoda1 treatment did not significantly affect the size or release of the small extracellular vesicles and resulted in only minor alterations to their proteomic profile. In myotubes Yoda1 treatment significantly increased small extracellular vesicles release and caused subtsantial alterations to the proteomic cargo. Notably, small extracellular vesicles released from both myoblasts and myotubes under PIEZO1 activation promoted myotube formation, though they did so through different capacities. Interestingly, in myotubes, Yoda1 also increased the expression of PIEZO1 protein of the vesicles suggesting a different biogenesis in undifferentiated and differentiated myogenic cells. Here, we propose PIEZO1 as a key element in controlling the release of small extracellular vesicles in myogenic precursors. Given the critical role of small extracellular vesicles in intercellular communication during muscle regeneration, our findings contribute to a better understanding of the role of PIEZO1 in the physiopathology of skeletal muscle tissue.

While lineage plasticity is a well-established driver of therapy resistance in prostate cancer, the role of tumor-infiltrating immune cells in mediating phenotype switching remains poorly understood. Here, we employed single-cell multi-omics to systematically characterize immune infiltration dynamics, transcriptional reprogramming, and intercellular communication networks during prostate cancer progression. Our analysis revealed that granulin (GRN)-expressing macrophages orchestrate the transition from adenocarcinoma (Adeno) to a therapy-resistant multilineage state exhibiting vimentin (VIM)+ mesenchymal and stem-like features through GRN/ tumor necrosis factor receptor superfamily member 1A (TNFRSF1A) interaction and the subsequent activation of the nuclear factor kappa-B (NF-κB) pathway. Intriguingly, these plastic tumor subclones reciprocally enhanced GRN expression in macrophages via colony stimulating factor 1 (CSF1) and CSF1 receptor (CSF1R) receptor-ligand axis, establishing a feedforward signaling loop that sustains lineage plasticity. Functional validation demonstrated GRN's critical role in driving epithelial-mesenchymal transition in vitro and conferring resistance to enzalutamide (ENZ) in patient-derived organoids. Therapeutic intervention studies in transgenic Adeno of the mouse prostate (TRAMP) models showed that CSF1R inhibition disrupted this vicious cycle, reducing GRN  + macrophages and suppressing multilineage subclone emergence. Spatial mapping revealed direct physical interactions between VIM  + tumor cells and GRN  + macrophages, while single-cell proteomics in castration-resistant patients confirmed the clinical relevance of this axis. Furthermore, we identified three novel stromal populations [decorin (DCN)+ endothelial cells, C-C motif chemokine ligand 7 (CCL7)+ fibroblasts, and interferon-induced protein with tetratricopeptide repeats 1 (IFIT1)+ neutrophils associated with disease relapse. These findings illuminate the tumor-immune crosstalk underlying treatment resistance and unveil promising therapeutic targets for overcoming lineage plasticity-driven resistance in advanced prostate cancer.

Late-onset combined immunodeficiency ( is a rare primary immunodeficiency characterized by hypogammaglobulinemia, T-cell lymphopenia, and susceptibility to opportunistic infections. While autoimmune liver involvement has been well documented in common variable immunodeficiency, no association with late-onset combined immunodeficiency has previously been reported. This case represents, to our knowledge, the first pediatric description of autoimmune hepatitis as the initial manifestation of late-onset combined immunodeficiency.

Intervertebral disc (IVD) degenerative disease is a prevalent and debilitating spinal disease. Current treatments only focus on symptomatic relief but fail to halt disease progression or restore the native biomechanical function of the spine. Regenerative medicine strategies, particularly those harnessing endogenous progenitor cells, offer a promising avenue for achieving biological repair and functional homeostasis. The identification of intervertebral disc progenitor cells (IVD-PCs) has unveiled a potential cellular reservoir for self-repair, given their demonstrated stemness attributes, including clonogenicity and multipotent differentiation. However, the clinical translation of IVD-PCs is significantly hampered by an incomplete understanding of their inherent heterogeneity, hierarchical organization, and, most critically, the dynamic interplay with their unique microenvironment, which dictates their fate decisions. This review synthesizes recent advances in deciphering the molecular signatures and functional plasticity of IVD-PCs. We place a particular emphasis on how key physicochemical, mechanical, and cellular cues within the IVD niche orchestrate progenitor cell behavior-ranging from maintenance and activation to aberrant differentiation-during both homeostasis and degeneration. Furthermore, we propose forward-looking insights to bridge critical knowledge gaps, aiming to propel the development of novel progenitor cell-based therapeutics for IVD degeneration.

In the absence of telomerase, telomere shortening triggers replicative senescence, a tumor suppressor mechanism that is also associated with oncogenic genomic instability. Yet, the precise mechanism that connects these seemingly opposing forces remains poorly understood. To directly study the complex interplay between senescence, telomere dynamics, and genomic instability, we develop a system in Saccharomyces cerevisiae to generate and track telomeres of precise length in the absence of telomerase. Using single-telomere and single-cell analyses combined with mathematical modeling, we identify a threshold length at which telomeres switch into dysfunction. A single shortest telomere below the threshold length is necessary and sufficient to trigger the onset of replicative senescence in a majority of cells. At population level, fluctuation assays establish that rare genomic instability arises predominantly in cis to the shortest telomere as Pol32-dependent non-reciprocal translocations that result in re-elongation of the shortest telomere and likely transient escape from senescence. The switch of the shortest telomere into dysfunction and subsequent processing in telomerase-negative cells thus serves as the mechanistic link between replicative senescence onset, genomic instability and the initiation of post-senescence survival.

Various signaling pathways are linked with osteogenesis and osteoarthritis progression. Bone Morphogenetic Protein 2 (BMP2), a key regulator within the TGF-β superfamily, is central to skeletal development through its ability to guide mesenchymal stem cells (MSCs) toward osteogenic and chondrogenic lineages. By activating canonical SMAD1/5/8 cascades alongside non-canonical MAPK branches (ERK, p38, JNK), BMP2 enhances transcriptional programs such as Runx2, thereby stimulating extracellular matrix synthesis, bone regeneration, and cartilage differentiation. Recombinant BMP2 (rhBMP2) has thus found clinical utility in spinal fusion and fracture repair. Yet its therapeutic translation is hindered by its paradoxical biology. Beyond regeneration, BMP2 provokes inflammatory signaling, upregulating cytokines like IL-6 and TNF-α, while driving catabolic enzymes (MMPs, ADAMTS) that degrade cartilage and intensify synovial inflammation, hallmarks of osteoarthritis (OA) progression. To address these limitations, current strategies emphasize fine-tuned regulation of BMP2 activity rather than broad stimulation. Emerging approaches include endogenous antagonists (Noggin, Gremlin), receptor decoys, selective BMPR1 blockade, spatiotemporally controlled delivery systems, and combinatorial use with stem cell or anti-inflammatory therapies. Such precision-based modulation aims to preserve BMP2's regenerative properties while suppressing its pathological consequences. Therefore, a deeper understanding of BMP2 signaling dynamics in joint biology is essential for unlocking safe therapeutic potential in OA management.

Oxygen therapy is required for the survival of premature infants with respiratory distress, yet hyperoxia exposure is a major contributor to alveolar developmental arrest in bronchopulmonary dysplasia (BPD). Despite the recognized role of fibroblasts in lung development, their functional contributions to the alveolar niche under hyperoxia remain poorly defined. Here, we profiled the involvement of fibroblasts using a BPD model induced by moderate hyperoxia (60% oxygen). Single-cell RNA sequencing (scRNA-seq) revealed that fibroblasts transitioned toward a disease-associated phenotype and exhibited enhanced communication with type II alveolar epithelial cells (AEC IIs) under moderate hyperoxia. Furthermore, activated fibroblasts increased the susceptibility of AEC IIs to hyperoxia via extracellular vesicles (EVs). These EVs were enriched with mitochondrial components, particularly the outer mitochondrial membrane (OMM) protein VDAC1. OMM-enriched EVs inhibited BNIP3-dependent mitophagy initiation in AEC IIs via VDAC1-GCN2 complex formation, leading to autophagic flux blockade and mitochondrial dysfunction. Inhibition of fibroblast-derived EV release using GW4869 or administration of human umbilical cord mesenchymal stem cell (hUC-MSC)-derived EVs attenuated hyperoxia-induced AEC II dysfunction and alveolar structural impairment. Taken together, our findings identify a fibroblast-epithelial communication mechanism that impairs mitochondrial homeostasis and leads to alveolar developmental arrest, highlighting a promising therapeutic target for BPD.

This study aimed to evaluate the differentiation potential of canine hepatic progenitor cells (cHPCs) derived from cryopreserved hepatocytes (cHeps). The cHeps were reprogrammed using three small molecules, Y-27632, A-83-01, and CHIR99021, to establish cHPCs. The cells were cultured on Matrigel in a chemically defined feeder-free maintenance medium for human pluripotent stem cells containing YAC, followed by 2% growth factor-reduced Matrigel. During culture, cHPCs transitioned from two-dimensional sheets to three-dimensional ductal structures. qRT-PCR and immunohistochemistry revealed increased CK19 expression on the ductal surfaces, indicating biliary epithelial-like differentiation. Overall, cHPCs possess a bipotential rematuration capacity. This study demonstrated that cHPCs induced by the YAC cocktail possess bipotent differentiation capabilities, confirming that their characteristics are likely to chemically induce liver progenitor cells.

Cell-to-cell communication is fundamental to life, with extracellular vesicles (EVs) playing a key role in intercellular signaling. Among them, small EVs (sEVs) have gained increasing attention as next-generation therapeutics. This review provides an overview of sEVs as therapeutic agents, comparing their advantages with cell-based and liposomal therapies, including unique benefits such as their enhanced ability to traverse biological barriers, ease of storage and administration, and their capability to utilize cellular machinery for fine-tuning therapeutic effects. Additionally, the therapeutic potential of sEVs from common human cell sources, including stem cells and immune cells, is discussed, highlighting their roles in modulating signaling pathways, cellular responses, and the microenvironment for treating cardiovascular, orthopedic, neurological, and autoimmune diseases, as well as cancer. Despite their promising outlook, challenges such as heterogeneity, extensive quality control requirements, systemic clearance, and scale-up limitations hinder clinical translation. Nonetheless, advancements in assay development, microfluidic models, computational databases, and bioengineering strategies continue to drive sEV-based therapies toward clinical and commercial viability.

Cellular senescence is increasingly recognized as a pivotal mechanism driving skeletal muscle aging and the development of sarcopenia, a condition characterized by the progressive loss of muscle mass, strength, and function. This review synthesizes recent evidence detailing the accumulation of senescent cells in aged skeletal muscle, including muscle stem cells (MuSCs), fibro-adipogenic progenitors (FAPs), immune cells, endothelial cells, and even post-mitotic myofibers. Senescence in these cell types impairs regenerative signaling, disrupts niche homeostasis, and propagates chronic inflammation. Emerging therapeutic strategies, termed senotherapeutics, aim to counteract these effects through senolytics (which eliminate senescent cells) and senomorphics (which modulate the senescence-associated secretory phenotype), as promising interventions to restore muscle function and delay sarcopenia. We will also discuss the remaining challenges and future directions for studying senescence in skeletal muscle.

Human induced pluripotent stem cell (iPSC) lines were generated from peripheral blood mononuclear cells (PBMCs) of four Korean patients with Huntington's disease using a non-integrating Sendai virus-based reprogramming method. The iPSC lines expressed pluripotency markers, as confirmed by immunocytochemistry (OCT4, NANOG, SSEA-4) and flow cytometry (TRA-1-60, TRA-1-81, SSEA-4), and showed trilineage differentiation potential in vitro. All lines retained normal karyotypes and short tandem repeat (STR) profiles identical to parental PBMCs, with complete clearance of Sendai virus. These patient-derived iPSCs provide a valuable resource for Huntington's disease modeling, drug discovery, and efficacy evaluation.

Chicken primordial germ cells (cPGCs) are a highly valuable resource for preserving chicken genetics and poultry biodiversity, as these diploid stem cells, derived from both male and female genotypes, can be maintained in long-term in vitro culture and are still capable of producing germline-transmitting progeny. However, the cryopreservation process, which guarantees that these cells can be used to maintain genetic resources, raises various questions about their quality after thawing. We assessed cryo-induced biological alterations in cPGCs derived from Lueng Hang Khao (LK), a Thai native chicken breed, using both Fourier transform infrared (FTIR) microspectroscopy along with traditional biological and molecular assays. Established male and female cPGC lines were cryopreserved for ≥ 2 weeks and assessed at day 10 and day 20 post-thawing against fresh control. The main findings of this study were that i) cryopreservation induced a transient decrease in viability and proliferation, while germ-cell gene markers remained stable in both sexes, ii) pluripotency markers in female cPGCs were more sensitive than in males, and more interestingly, iii) FTIR analysis of male cPGCs showed that cryopreservation induced biochemical changes. Those include membrane remodeling-increased lipid peroxidation, greater saturation and acyl-chain packing, and reduced unsaturation-with lipid accumulation that is most evident at day 20 post-thawing, suggesting a long-term effect. Additionally, a marked reduction of the ester C=O (∼1740 cm⁻1) band was also observed in cryopreserved cPGCs, suggesting constant modifications of key molecules. Concordantly, secondary-structure analysis indicated a shift toward native-like α-helical states, and nucleic-acid/carbohydrate signatures declined. These results highlight the overall post-thawing recovery of cPGCs and establish FTIR as a practical, label-free readout to complement standard assays, informing quality control and optimization of the quality of germ-cell biobanking.

The acquisition of totipotency requires transcriptional activation of endogenous retroviruses (MERVL/HERVL) and zygotic genome activation (ZGA) related genes, yet the molecular mechanisms linking chromatin architecture to this process remain elusive. Here, we demonstrate that mouse Dux and human DUX4, double homeobox transcription factors essential for totipotency, form liquid-liquid phase-separated (LLPS) condensates through conserved arginine residues within intrinsically disordered regions (IDRs) in the Homeobox domain. These condensates recruit CBP/p300 and CTCF to establish super-enhancers (SEs) at MERVL/MT2 loci, enabling H3K27ac deposition and chromatin accessibility. Hi-C analysis revealed that DUX-driven phase separation facilitates 3D genome reorganization, including de novo formation of enhancer-promoter loops and TAD boundary shifts. Disruption of LLPS (DUXR70A) abolished SE assembly, transcriptional activation, and embryonic chimerism. Strikingly, human DUX4 required phase separation for both myotoxic gene activation and cytotoxicity in facioscapulohumeral muscular dystrophy (FSHD) models. Our study establishes a paradigm wherein phase separation integrates transcriptional control with 3D genome remodeling to license totipotency, with direct implications for developmental biology and disease therapy.

Patients with triple-negative breast cancer (TNBC) experience high recurrence rates despite current interventions, which include radiation therapy (RT). Tumor cells thought to be involved in recurrence may survive in part due to their interactions with irradiated fibroblasts following treatment. How fibroblasts metabolically respond to RT and influence the behavior of TNBC cells is poorly understood. In this study, we demonstrate that irradiated fibroblasts undergo dynamic mitochondrial changes that are regulated by autophagy, resulting in a metabolic profile characterized by high levels of mitochondrial respiration and fatty acid oxidation. These metabolic adaptations lead to a secretory profile that induces an aggressive phenotype in TNBC cells that is mitigated when fibroblast autophagy is blocked. Our work reveals a burgeoning link between post-RT metabolic adaptations in fibroblasts and crosstalk with TNBC cells that promotes a microenvironment conducive to recurrence.

Lactate accumulates in large amounts in tumor cells due to the Warburg effect. However, the role of lactate-mediated lactylation, a post-translational modification, in regulating tumor immunity remains unclear. Here, we report that lactate-driven lactylation of STAT1 K193 inhibits interferon (IFN)-γ signaling pathway-mediated tumor immunity. Mechanistically, AARS1 lactylates STAT1 K193 and inhibits its binding to JAK2 and phosphorylation, thereby disrupting tumor responsiveness to IFN-γ, which leads to a reduction in the expression of downstream chemokines, including CXCL9, CXCL10, and CXCL11, ultimately facilitating immune escape of the tumor. Furthermore, we developed a cell-penetrating peptide, K193-pe, that can competitively inhibit STAT1 K193 lactylation and re-sensitize tumor cells to IFN-γ signaling, thus enhancing CD8+ T cell recruitment and improving the efficacy of immune checkpoint blockade therapy. Collectively, this study elucidates the functional significance of STAT1 K193 lactylation in tumor immunity and suggests that targeted inhibition of this modification, when paired with immunotherapy, may offer a viable treatment strategy.

The clinical use of bone graft materials for alveolar ridge preservation following tooth extraction has become a standard procedure to facilitate subsequent implant restoration and prosthetic rehabilitation. However, the therapeutic efficacy of these materials is substantially limited by their bio-inertness, lack of cellular activity, and unpredictable resorption rates. The development of bioactive osteogenic materials capable of host integration and active promotion of bone regeneration would represent a significant advancement over current clinical protocols. To address this challenge, our research has focused on developing bioactive biomaterials using human dental pulp stem cells (hDPSCs). This study proposes a novel strategy for alveolar ridge repair utilizing lyophilized hDPSC microspheres preconditioned through a three-dimensional (3D) dynamic osteogenic induction system. We cultured hDPSCs into 3D microspheres and subjected them to osteogenic induction within our established dynamic culture system, followed by lyophilization to prepare "off-the-shelf" osteogenic tissues. The resulting lyophilized microsphere constructs were implanted into fresh extraction sockets of SD rats and New Zealand white rabbits and evaluated over 4 weeks. Comparative analysis demonstrated that the lyophilized microsphere group exhibited significantly enhanced alveolar bone preservation, superior new bone formation, and improved bone microarchitecture compared to both control groups and traditional artificial bone powder groups. This preclinical study validates the potential of lyophilized hDPSC microspheres as an efficient and clinically promising bioactive material for post-extraction alveolar ridge reconstruction.

Intervertebral disc degeneration (IVDD) is the primary cause of chronic low back pain, with the senescence of nucleus pulposus cells (NPCs) as its core driving mechanism. Mitochondrial homeostasis acts as a critical mediator linking cellular stress responses to the senescence program of nucleus pulposus cells. Recent studies have indicated that the transplantation of apoptotic extracellular vesicles (ApoEVs) derived from the apoptotic mesenchymal stem cells (MSCs) represents a novel direction for tissue regeneration therapy. Given that the pathological microenvironment of IVDD exhibits hypoxic-inflammatory characteristics, the functional regulatory effects of ApoEVs pretreated under such conditions remain unclear. Here, we aimed to assess whether modulation of the MSCs culture microenvironment (hypoxia alone versus hypoxic-inflammatory conditions) generates ApoEVs (specifically I-ApoEVs) with enhanced therapeutic efficacy in the context of IVDD repair. A secondary focus of this study was to clarify the underlying mechanism through which such therapeutic effects are mediated by the regulation of mitochondrial homeostasis. Notably, the results demonstrated that I-ApoEVs were significantly superior to enhance the viability of NPCs and improve mitochondrial function. These findings suggest that the combined hypoxic-inflammatory pretreatment can more efficiently enhance the capacity of MSCs-derived ApoEVs to regulate mitochondrial homeostasis, thereby providing experimental evidence for optimizing ApoEV-based therapeutic strategies for IVDD.

Glioblastoma (GBM) is an aggressive primary malignant brain tumor in adults with a median patient survival of 12-18 months post-diagnosis, and no effective treatments, to date. The PI3K/Akt and Wnt/β-catenin signaling pathways promote GBM cell growth, survival, invasiveness and therapeutic resistance. We hypothesize that inhibiting Akt and β-catenin, which are central regulatory proteins of the PI3K/Akt and Wnt/β-catenin pathway, will suppress GBM growth and progression.

Repetitive mild traumatic brain injuries, common in contact sports like boxing, are recognized risk factors for long-term neurodegenerative conditions. There remains a clinical need for reliable, non-invasive biomarkers capable of detecting early brain alterations induced by repeated head trauma. This study evaluated the potential of neuron-derived exosomal microRNAs (miRNAs) as indicators of neuroinflammatory and neuroplastic changes in amateur boxers exposed to recurrent mild head impacts. Head impacts were measured across three weekly sparring sessions in ten male athletes. Neuron-derived exosomes were isolated from plasma samples collected both before (T0) and after (T2) the sparring period. The expression of eight miRNAs implicated in neuroplasticity and inflammation (miR-34a, miR-9, miR-124a, miR-223, miR-132, miR-126, miR-146a, and miR-146b) was analyzed using RT-qPCR. Sparring elicited a marked decrease in miR-126 levels and a significant increase in miR-34a, miR-132, miR-223, miR-146a, and miR-146b, suggesting a coordinated molecular response involving neuroinflammatory signaling, vascular dysregulation, and altered neuroplastic processes. Notably, the number of recorded head impacts correlated positively with miR-146a expression, supporting its potential role as a sensitive marker of neuronal stress. Bioinformatic analysis of miRNA target genes revealed enrichment in pathways associated with neurogenesis, axonal repair, synaptic remodeling, and brain-region-specific expression patterns characteristic of neural stem cells. Together, these findings support the potential use of neuron-derived exosomal miRNAs as peripheral biomarkers for early detection of sports-related brain injury, offering mechanistic insight into subclinical neural adaptations induced by repeated head trauma. Their implementation may contribute to minimally invasive monitoring strategies for athletes at risk.