Bone loss is the most common skeletal complication of childhood acute lymphoblastic leukemia (ALL) and seriously affects the long-term survival quality of children. However, the mechanisms behind bone loss are complicated and need to be elucidated. This study seeks to examine the principal parameters influencing the osteogenic development of bone marrow mesenchymal stem cells (BMSCs) in pediatric patients with B-cell acute lymphoblastic leukemia (B-ALL) experiencing bone loss, and to identify viable ways for alleviating bone loss.

Glioblastoma multiforme (GBM) is an aggressive, therapy-resistant brain tumor with limited treatment options. Epidermal growth factor receptor (EGFR) drives GBM pathogenesis. Here, we investigate ZYH005 (Z5), a brain-penetrant DNA intercalator with low systemic toxicity, as a novel therapeutic agent. Z5 potently inhibits the proliferation of GBM cell lines and patient-derived glioblastoma stem cells (GSCs) in vitro and suppresses tumor growth in orthotopic GSCs-derived mouse models, significantly prolonging survival without apparent toxicity. Mechanistically, Z5 exerts potent anti-GBM activity through a dual mechanism: DNA intercalation-induced damage and targeted inhibition of EGFR. By specifically inhibiting EGFR at E762, Z5 not only enhances DNA damage by suppressing the DNA damage response in the nucleus but also disrupts the interaction between nuclear EGFR and WEE1, leading to impaired WEE1/CDC2 signaling and G2/M checkpoint failure. Extranuclearly, Z5 further enhances its anti-GBM efficacy by inhibiting the canonical EGFR downstream pathways, mTOR, and ERK. These combined actions lead to cell cycle arrest and mitotic catastrophe. Our findings establish Z5 as a promising clinical candidate for classical GBM, employing a unique dual mechanism that overcomes EGFR-targeted and DNA-damaging therapy limitations by synergistically targeting DNA and EGFR with high efficacy, advancing understanding of EGFR-WEE1 biology, and supporting clinical development.

Mitochondria are nanoscale organelles essential for cellular metabolism and redox regulation, making them a compelling target for regenerative therapeutics. Analysis of wound-edge tissues from pediatric patients with chronic non-healing ulcers revealed marked metabolic insufficiency and impaired regenerative signaling, underscoring an unmet clinical need for mitochondrial-based interventions. Here, we show that topically applied mesenchymal stem cell-derived mitochondria (MSC-mt), functioning as naturally derived nanoscale organelles, markedly accelerate wound closure in a murine full-thickness skin injury model. MSC-mt enhanced angiogenesis, collagen deposition, and fibroblast survival while reducing oxidative stress and apoptosis. Mechanistically, their cytoprotective effects occur primarily through extracellular scavenging of reactive oxygen species (ROS), independent of cellular internalization. Excessive immobilization of MSC-mt within a thermosensitive hydrogel compromised their efficacy, emphasizing the importance of mitochondrial mobility and microenvironmental access. Under high oxidative stress, internalized MSC-mt activated PINK1-Parkin-mediated mitophagy, indicating a context-dependent intracellular quality-control response. These findings position MSC-mt as a cell-free, organelle-level nano-therapeutic that operates through a dual extracellular-intracellular mechanism and emphasize the importance of delivery strategies that preserve mitochondrial functionality and spatial freedom.

Male factors contribute to approximately half of all infertility cases globally, with heat stress recognized as a major environmental determinant of impaired male reproductive function. Extensive research indicates that heat stress disrupts spermatogenesis through multiple pathways, including testicular oxidative stress (OS), compromise of the blood-testis barrier, and dysregulation of the spermatogonial stem cell niche. As global temperatures rise, the prevalence of heat-induced reproductive impairment is increasing, underscoring the urgent need to identify safe and effective interventions that target the underlying oxidative damage. L-citrulline demonstrates significant potential in the field of male reproductive protection. However, existing reviews primarily focus on general discussions of antioxidants, lacking a systematic analysis of the specific mechanisms of L-citrulline. This review systematically synthesizes current knowledge on the molecular mechanisms of heat stress-induced oxidative injury in male gametes. Particular emphasis is placed on the multifaceted protective role of L-citrulline, which acts through synergistic mechanisms involving modulation of the arginine-nitric oxide (NO) pathway, preservation of mitochondrial homeostasis, restoration of autophagy flux, and suppression of apoptotic signaling. By integrating experimental and clinical evidence, this analysis aims to elucidate both the translational potential and the key scientific challenges of L-citrulline supplementation in male reproductive health. The review seeks to advance the translation of L-citrulline from basic research to clinical practice and to propose novel nutritional strategies for improving fertility outcomes in men exposed to heat stress.

Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) and Metabolic Dysfunction-Associated Alcohol-related Liver Disease (MetALD) exhibit systemic immune abnormalities. Given that such immune dysregulation is closely linked to the skeletal complications frequently observed in MASLD and MetALD, we sought to comprehensively characterize the bone marrow hematopoietic compartment and its link to osteoclastogenesis.

Male infertility due to spermatogenic failure remains a global challenge. While in vitro spermatogenesis (IVS) offers potential for fertility preservation, recapitulating the complex, species-specific testicular niche remains a formidable task. This review evaluates IVS progress and bottlenecks across rodents, primates, domestic animals, and humans.

Boerhavia elegans has long-held medicinal importance, yet its comprehensive phytochemical and biological characterization remains limited. This study provides the first integrated analysis combining HPLC, GC-MS, and molecular docking to correlate the chemical composition of B. elegans with its antioxidant and cytotoxic activities across different plant parts and solvent systems. Antioxidant assays revealed that polar leaf extracts exhibited the highest activity, with a DPPH IC50 value of 16.73 μg/mL. The methanolic stem extract showed the greatest phenolic content (25.89 mg GAE/100 mg), and the methanolic seed extract had the highest flavonoid yield (6.717 mg QE/100 mg). Ethyl acetate favored flavonoid extraction from the stem (18.29 mg QE/100 mg), while diethyl ether was most effective for the roots (10.21 mg QE/100 mg). UHPLC-DAD identified 15 phenolic compounds with detection limits ranging from 0.47 to 2.20 μg/mL. Cytotoxicity assays demonstrated strong inhibitory effects, with the methanol leaf extract showing 82.5% inhibition of HepG2 cells and the ethyl acetate root extract inhibiting 83.55% of MCF-7 cells. The hexane leaf extract produced the highest inhibition (88.8%) of MDA-MB-231 cells. GC-MS analysis revealed bioactive molecules such as phytol, stigmasterol, and hexadecanoic acid, which were further validated by molecular docking interactions with vimentin and BCL-2 proteins, suggesting potential anticancer mechanisms.

The purpose of the study was to discuss the role of molecular imaging in stem cells (SCs) therapy and SC tracking with the special focus on nuclear medicine (NM) applications.

Small extracellular vesicles (sEVs) have emerged as central mediators of intercellular communication in the central nervous system (CNS) and are increasingly recognized for their dual roles in the pathogenesis and treatment of neurodegenerative diseases (NDDs). In disease contexts, sEVs facilitate the intercellular dissemination of pathogenic proteins and nucleic acids, thereby contributing to the propagation of Alzheimer's disease (AD) and Parkinson's disease (PD) pathology. Conversely, their intrinsic biocompatibility, capacity to traverse brain barriers, and inherent organotropic properties position sEVs as highly promising nanocarriers for CNS drug delivery. While mesenchymal stem cell-derived sEVs have been widely investigated in preclinical NDD models, accumulating evidence suggests that sEVs derived from neural cells, including neural stem cells, neurons, astrocytes, microglia, oligodendrocytes, and brain endothelial cells may offer superior brain targeting, disease relevance, and functional efficacy. This review provides a comprehensive and critical analysis of current knowledge on neural cell-derived sEVs, encompassing their physiological roles in brain homeostasis, their involvement in AD and PD pathogenesis, and their emerging therapeutic applications. We discuss cell-type-specific sEV cargo profiles, mechanisms underlying blood-brain and blood-cerebrospinal fluid barrier traversal, and recent advances in endogenous and exogenous engineering strategies that enhance cargo loading, targeting precision, and therapeutic performance. Importantly, we address key translational challenges that currently limit clinical implementation. By integrating mechanistic insights with therapeutic and engineering perspectives, this review highlights neural cell-derived sEVs as a biologically informed and versatile platform, underscoring their potential to advance next-generation neuro-nanomedicine for NDDs.

An experimental study on scaffold characterization and animal study.

The liver is essential for maintaining metabolic functions, detoxification, and homeostasis. It is crucial to recognize any malfunction in patients with liver disease/failure. To better understand disease pathology, a combination of clinical investigation and emerging technologies, such as organoid models, provides powerful tools for advancing disease studies. There are limitations in animal models, and conventional twodimensional (2D) cultures have hindered accurate modeling of liver physiology and pathology. Liver organoids, three-dimensional, self-organizing structures produced using pluripotent or adult stem cells, have increased prominence as advanced in vitro systems that recapitulate the architecture, cellular heterogeneity, and functionality of native liver tissue. This review explores the formation and cellular sources of liver organoids, such as multi-type cell and single-type cell systems, and highlights the role of engineered extracellular matrices and bioactive signaling pathways in their formation. We further address the integration of advanced technologies, for example, CRISPR/Cas9, viral transduction, three-dimensional (3D) bioprinting, and a liver-on-achip platform, which have revolutionized the customization and application of liver organoids. Their utility in drug screening, modeling liver diseases, such as genetic, infectious, and fibrotic conditions, and also applications in regenerative medicine are discussed. Liver organoids depict a transformative tool for understanding liver tissue pathophysiology, screening therapeutics, advancing personalized medicine, and tissue engineering.

Exposure to silver nanoparticles (AgNPs) poses potential health risks. Epigenetic alterations are increasingly recognized as a critical mechanistic bridge between environmental stressors and adverse toxicological outcomes. Here, we demonstrate that exposure to noncytotoxic concentrations of AgNPs induces significant genome-wide alterations in DNA hydroxymethylation in mouse embryonic stem cells, which primarily is mediated by TET dioxygenase-dependent pathways. Further investigation shows that AgNPs activate TETs through a reactive oxygen species (ROS)-dependent manner, independent of the Ag+ ion. Our findings provide evidence that AgNPs disrupt TET-mediated DNA demethylation and reveal a novel epigenetic mechanism by which nanoparticles perturb DNA methylation homeostasis during early embryonic development.

The study outlines principles and workflows for a comprehensive extractables and leachables qualification trial of microcarriers for use in a cell therapy application. Styrene-based MCs were qualitatively and quantitatively analyzed in accordance with USP 〈665〉, followed by a kinetic investigation. Extractables data were fitted to an algorithm to enable reconstructive modeling of dynamic experimental data for both stable and degradable extractables. In a subsequent step, the temporal exposure to process equipment-related leachables (PERLs) was modeled for MCs used in a hypothetical cell therapy application with partial and continuous medium exchange. The results demonstrated that, in a dynamic environment, the release of PERLs from MCs in a perfused system does not influence product quality at levels that would pose a patient safety risk. Furthermore, process concentrations remain significantly below exposure levels that could have detrimental effects on therapeutic human cells. This demonstrates the benefits of perfused systems, or systems with partial medium exchange, as the washout effect dominates PERL release rates. PERL concentrations in such dynamic systems will always be significantly lower than PERL equilibrium concentrations under static, stagnant conditions.

Remote ischemic postconditioning (RIPC) confers neuroprotection in ischemic stroke partly via promoting angiogenesis and neurogenesis, but its precise molecular mechanisms remain unclear; here, we investigated the role of the secreted guidance protein Netrin-4 (NTN4) and its upstream regulator hypoxia-inducible factor 1α (HIF-1α) in mediating RIPC's reparative effects, using endothelial-specific Ntn4 knockout (KO) mice subjected to transient middle cerebral artery occlusion (MCAO) and RIPC, alongside in vitro assays with brain microvascular endothelial cells (BMECs) and neural stem cells (NSCs) and molecular interaction analyses, including DNA pull-down and chromatin immunoprecipitation (ChIP), finding that RIPC significantly upregulated NTN4 expression in the ischemic penumbra of MCAO mice, that endothelial-specific Ntn4 knockout abolished RIPC's protective effects-impairing neurological recovery, angiogenesis and neurogenesis, which were rescued by recombinant NTN4 administration, that NTN4 promoted BMEC proliferation and tube formation via an integrin β1-PI3K/AKT pathway while conditioned medium from Ntn4-overexpressing BMECs enhanced NSC neuronal differentiation through an integrin β1-MAPK/ERK axis, and that RIPC stabilised HIF-1α, which directly bound the Ntn4 promoter to drive its transcription, collectively establishing that RIPC orchestrates brain repair by stabilising HIF-1α to transcriptionally activate endothelial NTN4, which signals through integrin β1 to drive parallel PI3K/AKT and MAPK/ERK pathways for angiogenesis and neurogenesis, highlighting this axis as a key therapeutic target in stroke.

Nanovesicles (NVs)-generated directly from donor cells-have emerged as important mediators of intercellular communication, drug delivery devices, and in therapeutic applications, including regenerative biology. Top-down strategies to enhance the potential regenerative efficacy of NVs following cell hypoxic stress are poorly understood. Here, NVs were generated using rapid extrusion directly from human induced pluripotent stem cells (iPSC) under basal and hypoxic-associated conditions, identifying select pluripotent/stem cell maintenance markers associated with NV composition. We performed adaptive cellular remodeling of iPSC to hypoxic preconditioning over 2, 4, and 6 h, demonstrating that NV form and composition are context-dependent on hypoxia and its duration. Hypoxic exposure modifies the NV temporal protein landscape of networks involved in wound healing (FLNA, MYH9, ACTC1), hypoxia response (HMOX2, HMOX1, PGK), extracellular matrix remodeling (ITGA6, MFGE8, ITGB1), and tissue repair (HSP A5/A8/H1/20/27/70/90, GJA1, HMGB1, ILK). Importantly, we highlight that the NV proteome is dependent and highly consistent on temporal exposure of donor cells to hypoxia, indicating a platform to regulate NV phenotype, tailored toward their potency. Here, we show NVs exhibit a distinct proteome landscape associated with regulation in reactive oxygen species generation and cell/tissue survival (enhanced 2-4 h hypoxia), wound healing and angiogenesis (enhanced 4-6 h hypoxia), and tissue repair, hypoxic response, and metabolic/energy production (enhanced 6 h hypoxia). Extended hypoxic cell exposure (at 4-6 h) regulates NV function in a hypoxic time-dependent manner, with NVs significantly promoting tubule formation of endothelial cells in hypoxic conditions (p < 0.0001). Here, we detailed the capacity of hypoxic cell conditioning to mediate NV phenotype and function in a temporal manner as a platform to enhance functional and potential regenerative therapeutic efficacy of NVs.

Skin photoaging, clinically characterized by wrinkles and hyperpigmentation, accounts for 80% of extrinsic aging. Chronic UV exposure drives this process via oxidative damage. However, its synergistic axis with mitochondrial dysfunction remains mechanistically elusive. This study aims to elucidate the mechanistic link between mitochondrial oxidative stress and UV-induced photoaging, focusing on reactive oxygen species overproduction as a central driver of cellular decline.

Stem cell transplantation (SCT) holds significant promise for regenerative medicine, yet immune rejection remains a major obstacle. To address this, recent advances leverage CRISPR/Cas9 to engineer hypoimmunogenic induced pluripotent stem cells. These modified cells lack classical immune recognition markers (HLA class I/II) yet retain immune-tolerant molecules such as HLA-E, HLA-G, and CD47, enabling their universal use across different individuals. Additionally, mesenchymal stem cell-derived exosomes and immune checkpoint modulators (e.g., PD-L1) have shown clinical effectiveness by reducing graft-versus-host disease and autoimmune reactions. They achieve this through mechanisms such as suppressing inflammatory T-cell activation, promoting regulatory T-cell expansion, and modulating macrophage polarization. Despite these advances, several challenges remain. One key concern is the potential tumorigenic risk caused by genomic instability during genome editing and long-term cell expansion. Emerging precision editing platforms, including base editing and prime editing, provide strategies to reduce double-strand DNA break-induced chromosomal rearrangements and improve genomic safety. Future research priorities include integrating AI-based immune profiling, precision genome editing, and advanced 3D-bioprinting technologies. Together, these innovations represent a paradigm shift toward developing safer, more effective, universally compatible stem cell therapies for diseases previously deemed untreatable.

Hal E. Broxmeyer profoundly shaped modern hematopoietic stem cell biology through a rigorously functional approach that defined stem and progenitor cells by what they do rather than how they appear. Across five decades, his work established a unifying principle: biological mechanisms matter most when they preserve or enhance durable, multilineage hematopoietic reconstitution, particularly in transplantation. This function‑first philosophy guided seminal contributions spanning cytokine regulation of hematopoiesis, umbilical cord blood transplantation, stem cell mobilization, and the biology of hypoxia. Broxmeyer helped define hematopoietic regulation as emerging from a complex, context‑dependent "sea of cytokines," challenging reductionist models that assigned fixed roles to individual factors. This conceptual framework informed translational advances, including the identification of dipeptidyl peptidase‑4 (DPP4/CD26) as a key regulator of chemokine activity, stem cell homing, mobilization, and engraftment, ultimately influencing clinical mobilization strategies and cord blood transplantation outcomes. His pioneering demonstration that human umbilical cord blood contains functionally competent hematopoietic stem cells transformed discarded biological material into a globally used graft source. Equally transformative was his recognition of oxygen tension as a critical, often overlooked determinant of stem cell integrity. By defining extraphysiological oxygen shock/stress (EPHOSS), Broxmeyer revealed how routine handling conditions compromise stem cell function and identified mechanistic strategies to preserve engraftment capacity. Together, these contributions reshaped experimental standards, aligned basic discovery with clinical reality, and trained generations of scientists to prioritize functional validation. Broxmeyer's legacy endures not only in clinical practice worldwide, but in a way of thinking that anchors discovery to biological and therapeutic relevance. TEASER ABSTRACT: Hal E. Broxmeyer helped define modern hematopoietic stem cell biology through a singular guiding principle: stem and progenitor cells must ultimately be judged by function durable, multilineage hematopoietic reconstitution rather than phenotype alone. This tribute synthesizes five decades of his scientific impact across cytokine biology, umbilical cord blood transplantation, stem cell mobilization, DPP4/CD26-mediated regulation of homing and engraftment, and the recognition of hypoxia and extra-physiologic oxygen stress as critical determinants of stem cell integrity. From conceptualizing hematopoietic regulation as a context-dependent "sea of cytokines," to establishing umbilical cord blood as a clinically viable graft source, to translating mechanistic insights into mobilization and engraftment strategies, Broxmeyer consistently linked molecular discovery to transplantation-relevant outcomes. His work reshaped experimental standards, clinical practice, and translational thinking in hematology. In an era increasingly dominated by descriptive depth, his legacy remains a powerful reminder that the highest measure of discovery is enduring biological function.

Cancer stem cells represent a critical cell population that drives the malignant proliferation and invasiveness of glioblastoma (GBM), contributing to its poor prognosis. However, the mechanisms underlying the maintenance of stemness in GBM is poorly understood. In this study, we identified Rho guanine nucleotide exchange factor 26 (ARHGEF26) as a protein enriched in GBM stem cells and GBM tissues. High expression of ARHGEF26 was associated with shorter survival in patients with GBM. Functionally, ARHGEF26 enhanced the self-renewal, invasion, and tumorigenesis of GBM cells both in vitro and in vivo. Mechanistically, ARHGEF26 interacted with and stabilized the core stemness transcription factor SOX2 by reducing its K48-linked poly-ubiquitination and subsequent proteasomal degradation. Our findings reveal a novel role and mechanism for ARHGEF26 in promoting GBM stemness and suggest its potential as a therapeutic target.

Congenital long QT syndrome (LQTS) is a heritable cardiac channelopathy with increased risk of cardiac-triggered syncope/seizures, sudden cardiac arrest, and sudden cardiac death.