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.

Radiation-induced intestinal injury (RIII) is a serious and common complication of radiotherapy, and there are currently no effective therapeutic strategies. This study investigates the protective role of 4-octyl itaconate (4-OI), a cell-permeable itaconate derivative, against RIII. In vitro, 4-OI pretreatment enhanced the viability of irradiated intestinal epithelial cells, reduced reactive oxygen species (ROS) accumulation, and alleviated DNA damage. In a murine model of total body irradiation, 4-OI administration mitigated intestinal structural disruption, promoted crypt stem cell regeneration, and suppressed epithelial apoptosis. Mechanistically, 4-OI exerted its cytoprotective effects by modulating the SLC7A11/GPX4 axis to inhibit ferroptosis and enhancing glutathione biosynthesis. Furthermore, 16S rRNA sequencing revealed that 4-OI treatment recalibrated radiation-induced gut microbiota dysbiosis, suggesting an additional microbiome-mediated protective pathway. To our knowledge, the results represent the first demonstration of 4-OI's protective effects in RIII pathogenesis, positioning it as a novel therapeutic candidate for clinical radioprotection through dual mechanism targeting.

Ischemic stroke is often linked to increased oxidative stress, impaired autophagy, and resultant cellular injury. This study examines the correlation between autophagy-mediated cellular injury and the use of a hydrogen sulfide (H2S)-releasing peptide, SV-E4, to mitigate cellular damage resulting from oxygen-glucose deprivation (OGD), an in vitro model simulating ischemic stroke. The research employs neuroblastoma (N2a) and microglial (BV2) cell lines as well as 3-day developed chicken embryos. Elevated levels of pro-autophagic proteins corroborate our study's findings that OGD markedly enhances oxidative stress and triggers autophagy. Administration of the SV-E4 peptide formulation to cells subjected to OGD significantly reduced the amounts of reactive oxygen species. In the present investigation, dihydroethidium, Amplex Red, 2',7'-dichlorofluorescin diacetate, and mito-SOX were all utilized to corroborate conclusion. Decreased levels of autophagy markers indicated that the SV-E4 formulation could prevent aberrant autophagy. Notably, this mechanism is not limited to ischemic stroke but extends to other ischemia-reperfusion models, as demonstrated using an in ovo ischemia-reperfusion model in chicken embryos. Altogether, the results indicate that the SV-E4 peptide has a beneficial impact on preventing excessive oxidative stress and autophagy, demonstrating its potential as a treatment approach for individuals with ischemic stroke.

Human naïve pluripotent stem cells (nPSCs) can be induced by various combinations of signaling factors to generate blastocyst-like structures, termed blastoids. Despite rapid progress in human blastoid models, their potential to uncover fundamental mechanisms of early human development remains limited, leaving key morphogenetic processes poorly understood. Here, we describe a simple and robust system in which dimethyl sulfoxide (DMSO) alone induces blastoid formation from human nPSCs. This model recapitulates key pre- and post-implantation features and exhibits enhanced polar trophectoderm (TE) organization, more efficient attachment within an implantation-relevant window, improved epiblast lumenogenesis associated with amniotic cavity formation, and more robust, sustained expansion of embryonic lineages following attachment. Using this system, we reveal a previously unrecognized mechanism underlying TE cavitation and identify lysosome-associated genes - particularly subunits of the proton pump V-ATPase - as essential regulators of blastoid cavitation. DMSO treatment upregulates key V-ATPase subunits (ATP6V0A4 and ATP6V1B1), which are also enriched in the TE of human embryos. Genetic or pharmacological inhibition of V-ATPase activity disrupts lysosomal acidification, blocks intracellular vacuole formation, and impairs blastoid cavitation, whereas overexpression of V-ATPase subunits rescues this phenotype. Furthermore, genetic and pharmacological perturbations of V-ATPase function significantly compromise cavitation in both mouse and human blastocysts. Finally, DMSO treatment induces membrane biomechanical changes characteristic of early embryonic development, suggesting a mode of action distinct from conventional small-molecule, signaling pathway-based induction strategies. This simple DMSO-based blastoid model recapitulates key aspects of human blastocyst development and reveals a conserved requirement for V-ATPase-mediated lysosomal acidification during early mammalian embryogenesis.

Open tibial fractures with major bone loss, especially from high-energy trauma, are prone to atrophic nonunion, pseudoarthrosis, infection, and limb shortening. Standard methods like Ilizarov fixation often fail when healing is poor or infection persists, making adjunctive biological therapies necessary. Although the Ilizarov technique is established for tibial nonunion, evidence on mesenchymal stem cell (MSC)-rich bone marrow injections remains limited. We reported 2 young male patients with open tibial fractures and substantial bone loss. Both were initially managed with Ilizarov fixation for 7 - 8 months but subsequently developed atrophic nonunion, pseudoarthrosis, persistent infection with fistula, and limb shortening. Examination showed abnormal motion and absence of bone fragments, and labs confirmed ongoing infection. The definitive management involved a staged surgery, augmented by dual intraosseous injections of autologous MSC-rich bone marrow. This protocol successfully achieved bony union. The Ilizarov frame was then replaced with an AO fixator for consolidation. Both patients regained full limb length and infection resolution, with minor fibrotic tissue formation. Tibial pseudoarthrosis with infection and bone loss is challenging. In our cases, combining Ilizarov distraction with MSC-rich marrow enhanced osteogenesis, leading to union in a shorter time and full recovery. This synergy highlights the potential of regenerative strategies in complex orthopedic trauma.

The pituitary gland plays a central role in maintaining physiological homeostasis by secreting multiple hormones that regulate diverse body functions. Dysregulation of pituitary hormones can arise from various conditions, such as pituitary tumors and autoimmune diseases, leading to a broad spectrum of symptoms. During embryonic organogenesis, the pituitary gland originates from the oral ectoderm in close contact with the adjacent hypothalamus. This tissue interaction is essential for proper development. Although the molecular mechanisms underlying pituitary development and related disorders have been extensively studied using animal models, such as rodents and zebrafish, species-specific differences limit the translatability of these findings to humans. Moreover, the scarcity of established human pituitary cell lines has hindered the investigation of human-specific mechanisms. Recent biotechnological advances have addressed these limitations by enabling the long-term culture of human pituitary tumor tissues and in vitro generation of pituitary hormone-producing cells from human pluripotent stem cells. These emerging platforms provide powerful tools for deepening our understanding of pituitary biology and diseases. In this review, we summarize current in vitro experimental models derived from pituitary tissues and pluripotent stem cells and discussed their applications in the study of pituitary development, physiology, and related disorders.

The CXCR4/CXCL12 signaling axis plays a central role in regulating immune cell trafficking, hematopoietic homeostasis, and organogenesis. However, dysregulation of this axis contributes to the pathogenesis of numerous disorders, highlighting CXCR4 inhibition as a promising therapeutic strategy. Mavorixafor, the first orally available small-molecule CXCR4 antagonist, recently received FDA approval for WHIM syndrome (Warts, Hypogammaglobulinemia, Infections, and Myelokathexis) and is currently being developed for additional indications. Despite extensive research on CXCR4 biology, a comprehensive analysis of mavorixafor's pharmacologic profiles and its performance in preclinical and clinical settings is lacking. This systematic review synthesizes the pharmacology, efficacy, and safety of mavorixafor, summarizing evidence from various sources, including PubMed/MEDLINE, Web of Science, Google Scholar, conference proceedings, clinicaltrials.gov, and FDA resources. Mavorixafor demonstrates potent CXCR4 antagonism, rapid oral absorption, and a long half-life, enabling once-daily dosing. Clinically, it has been shown to increase neutrophil counts and reduce infection rates, contributing to its approval for WHIM syndrome. Early clinical studies in chronic neutropenia indicate sustained neutrophil elevation and decreased dependence on G-CSF. Additionally, emerging data suggest potential benefits in specific malignancies and its utility in mobilizing hematopoietic stem and progenitor cells, as well as in other immune-mediated disorders related to CXCR4 dysregulation. Furthermore, this review positions mavorixafor within the broader CXCR4-targeted therapeutic landscape, identifying current research gaps and suggesting directions for future studies. In conclusion, by integrating mechanistic insights with preclinical and clinical findings, this article highlights mavorixafor's promise as a targeted therapy with the potential to transform treatment paradigms for CXCR4-driven diseases.

Cell mechanics, elasticity and viscoelasticity, are key markers of biological states like cancer. Atomic force microscopy (AFM) is ideal for such studies, but its low throughput limits large-scale use. Two solutions exist: automation for higher throughput, or high-density measurements for richer data. The latter enables machine learning (ML)-based classification, with viscoelastic parameters offering unique insights beyond static measures like Young's modulus.

The global aging crisis presents significant challenges in treating age-related skeletal disorders, characterized by impaired bone regeneration due to senescent microenvironment dysfunction. While anti-senescence drugs have shown promising therapeutic potential, their clinical use is hindered by severe side effects and limited regenerative efficacy. Biomaterials-based anti-senescence strategies offer a promising alternative. This study is the first to demonstrate that silicate bioceramics possess not only osteogenic properties but also intrinsic anti-senescence capabilities, laying the foundation for the concept of "Silicate Anti-Senescence (SAS)". Using hardystonite (Ca2ZnSi2O7, ZnCS), one of the classic silicate-bioceramics, we reveal its biphasic biological function-delaying cellular senescence and promoting bone formation-through various formulations, including porous scaffolds, ionic extracts, and particle suspensions. In vitro, ZnCS effectively delays senescence of bone marrow mesenchymal stem cells (BMSCs) and enhances osteogenic differentiation. In vivo, ZnCS 3D scaffolds remodel the senescent microenvironment and accelerate osteoporotic bone regeneration, while oral administration of ZnCS particles exhibits significant anti-osteoporotic effects. Mechanistically, Zn2+ and SiO32- ions released from ZnCS exert synergistic effects that converge on the PI3K-AKT-SIRT1 signaling axis, thereby attenuating senescence-associated programs and reinforcing osteogenic gene networks. Notably, compared to classic anti-senescence drugs (dasatinib and quercetin), ZnCS shows superior performance compared to the control groups in both anti-senescence and osteogenesis. The study provides new insights into developing anti-senescence strategies for age-related skeletal diseases with silicate-based bioceramics.

Autologous hematopoietic stem cell transplantation (AHSCT) is an established therapy for diffuse progressive systemic sclerosis (DpSSc), improving progression-free and overall survival compared with cyclophosphamide; however, relapse occurs in ∼12-17% of patients. Chimeric antigen receptor T cell (CAR-T) therapy offers a novel approach to deplete autoreactive B cells. This study aimed to assess the feasibility, efficacy, and safety of anti-CD19 CAR-T therapy as a rescue treatment in patients with SSc relapse following AHSCT.

Previous studies have shown that the lung tissues of preterm infants with bronchopulmonary dysplasia (BPD) are infiltrated by pro-inflammatory macrophages. The Wnt5a/frizzled-5/CaMKII signaling pathway plays a critical role in regulating macrophage activation. The antimicrobial peptide LL37, an important paracrine factor secreted by cord blood mesenchymal stem cells, modulates macrophages. Lower LL37 levels are associated with a higher risk of BPD. However, whether LL37 protects against inflammation-induced lung injury and its underlying mechanisms remain unclear.

Zinc is a component of the antioxidant defense system. Its functions protecting biological systems from oxidation are exerted at multiple levels including competing with redox active metals for binding sites, dynamically interacting with thiol groups and inducing metallothionein (MT) expression, regulating oxidant production, and increasing antioxidant defenses in part via NRF2 modulation. Zinc also directly and indirectly modulates redox regulated signaling cascades. Zinc deficits can affect not only the capacity of cells to defend against oxidative challenges but also alter redox signaling that modulate key cellular processes. Zinc is essential at different stages of development given its capacity to regulate key participating processes, e.g. cell proliferation, differentiation and survival. In the developing brain, the adverse consequences of a decrease in zinc availability depend on the severity and the timing of the deficiency. While gestational severe zinc deficiency causes teratogenesis in the brain and several other organs, mild zinc deficiency has significant deleterious consequences on the neural stem cell pool, neurogenesis, oligodendrogenesis, and astrogliogenesis in the offspring. Alterations in neuron, oligodendrocyte and astrocyte number, neuronal specification and myelination associated with zinc deficits in early development persist into adulthood, affecting behavior and motor performance. This review will focus on the role of zinc on brain development and on the interconnection between zinc and the redox tone in shaping different windows of neurodevelopment.

Bone marrow organoids (BMOs) are three-dimensional cell culture models that recapitulate key structural and functional features of the bone marrow (BM) niche. BMOs offer important advantages in hematopoietic research by modeling key aspects of human hematopoiesis compared to classical in vitro two- and three-dimensional cellular models including bioreactors, BM-on-a-chip platforms, 2D models or BM ossicles by better recreating the three-dimensional architecture, cellular heterogeneity, and spatial organization of the BM microenvironment. They offer a scalable and cost-effective alternative to animal models and reduce the need for animal experiments. Induced pluripotent stem cell (iPSC)-derived BMOs can be generated from a patient's own cells, enabling personalized disease modeling and drug testing and are highly amenable to gene editing technologies allowing precise modifications to study gene function or model diseases. Recent landmark studies from Christoph Klein and Abdullah Khan have established protocols for the generation of BMOs and demonstrated their applications in disease modeling. Here, we review the critical steps in BMO generation, their structural/ functional validation and discuss how BMOs can be applied to model inflammatory responses, rare genetic bone marrow failure syndromes, and multiple myeloma. These advances demonstrate BMOs' growing potential as powerful tools in hematopoietic research and will pave the way for further innovation and increasingly refined systems in future studies.

Regenerative medicine increasingly relies on therapeutic cells such as mesenchymal stem cells (MSCs), induced pluripotent stem cells (iPSCs), and engineered cellular constructs to repair and restore damaged tissues. However, clinical translation is constrained by challenges in maintaining viability, ensuring precise localization, achieving durable engraftment of transplanted cells, and producing enough clinically relevant cells at scale. Microfluidic technologies are emerging as transformative tools to address these barriers by enabling precise manipulation of fluids, biomaterials, and cells at the microscale. In the context of therapeutic cell delivery, these platforms can improve early retention and engraftment compared with conventional needle injection, tighten control over delivered cell dose, preserve viability under defined shear conditions, enable site-specific placement of cell-laden carriers, and support immunoisolating or immunomodulatory architectures that enhance immune safety. These platforms provide controlled microenvironments that mimic native tissue architecture, regulate biochemical and mechanical cues, and support scalable production of cell-laden carriers. Advances in microfabrication, from soft lithography and thermoplastics to 3D printing and hydrogel integration, have expanded device versatility, while embedded sensors allow real-time monitoring of cell state, metabolism, and differentiation. Beyond single-cell delivery, microfluidics facilitates encapsulation, co-culture, and organoid assembly, enabling multicellular systems with physiologically relevant interactions. Coupled with CRISPR genome editing and synthetic biology, these platforms allow the engineering of "smart" therapeutic cells with enhanced regenerative and immunomodulatory functions. Applications extend to microfluidic sorting for stem cell purification, controlled differentiation, and advanced manufacturing of immune cell therapies such as Chimeric Antigen Receptor (CAR)-T cells, alongside exosome-based strategies for precision delivery. Despite promising progress, obstacles remain in regulatory standardization, large-scale manufacturing, and integration with clinical workflows. This review highlights state-of-the-art microfluidic approaches for controlled delivery of stem cells and engineered cells, emphasizing how these systems impact key delivery metrics such as retention, dose control, shear resilience, spatial targeting, and immune interfaces to advance precision and personalized regenerative medicine.

Ovarian aging, which progresses faster than overall organismal aging, represents a major public health challenge, profoundly impacting female reproductive health and accelerating societal aging. The traditional Chinese medicine formula Zuogui Pill (ZGP) has shown great potential in delaying ovarian aging, warranting further investigation and development.