Hypertrophic cardiomyopathy (HCM) is a prevalent inherited cardiac disorder characterized by left ventricular hypertrophy and contractile dysfunction. Mutations in sarcomeric genes, particularly cardiac myosin-binding protein C (MYBPC3), are a leading cause of HCM. Here, we generated two induced pluripotent stem cell (iPSC) lines from peripheral blood mononuclear cells of patients carrying distinct MYBPC3 mutations (c.2490dupT and c.1800delA). Both lines displayed normal morphology, stable karyotypes, robust expression of pluripotency markers, and trilineage differentiation potential. These patient-specific iPSC lines provide a valuable platform for modeling MYBPC3-associated HCM and enable mechanistic and therapeutic studies of inherited cardiac disease.

Loeys-Dietz syndrome (LDS) is a rare autosomal dominant connective tissue disorder caused by pathogenic variants in genes involved in the TGF-β signaling pathway. Here, we report the generation of a human induced pluripotent stem cell (iPSC) line derived from peripheral blood mononuclear cells (PBMCs) of an LDS patient carrying a heterozygous TGFBR1 mutation (c.679G > A, p.Glu227Lys). The iPSC line exhibits normal morphology, expresses pluripotency markers, maintains chromosomal integrity, and demonstrates trilineage differentiation capacity. This patient-specific iPSC line provides a valuable platform for modeling LDS pathogenesis and investigating vascular disease mechanisms.

Cranial sutures are dynamic growth sites that balance bone growth with mesenchymal patency to accommodate cranial expansion during development. While intramembranous ossification has traditionally been considered the default mechanism of suture fusion, accumulating evidence demonstrates that endochondral pathways might also play a significant role under both physiological and pathological conditions. In this review, we contrast normal developmental ossification processes with premature fusion in craniosynostosis, integrating histological, molecular, and imaging data. We highlight the context-dependent nature of cranial suture biology, influenced by embryonic origin, local signalling gradients, and genetic perturbations. Recognizing divergent ossification mechanisms reframes our understanding of both normal and premature suture fusion and has clinical implications for mechanism-specific therapeutic strategies. Finally, we outline areas for future investigation, including high-resolution profiling of human sutures across developmental stages, to establish a normative framework for cranial suture biology and inform mechanism-driven regenerative approaches.

Cytotoxic chemotherapy primarily targets rapidly proliferating cancer cells but also depletes normal myeloid cells. The resulting cell loss triggers reactive myelopoiesis, a compensatory process in which hematopoietic stem and progenitor cells (HSPCs) in the bone marrow (BM) regenerate myeloid lineages. We previously showed that the alkylating agent cyclophosphamide (CTX) induces myelopoiesis leading to the expansion of immunosuppressive monocytes in mice. However, the molecular features and clinical relevance of these cells remain poorly understood. Here, we report the emergence of immunosuppressive monocytes in the peripheral blood of lymphoma patients receiving CTX-containing chemotherapy. To gain mechanistic insight into CTX-induced myelopoiesis, we performed single-cell RNA sequencing (scRNA-seq) and assay for transposase-accessible chromatin using sequencing (ATAC-seq) on BM monocytes from CTX-treated mice. These analyses revealed a heterogeneous monocyte population and demonstrated that CTX skews myelopoiesis toward the generation of neutrophil-like monocytes (NeuMo). Moreover, CTX-induced NeuMo cells, enriched within the CXCR4⁺CX3CR1⁻ monocyte subset, exhibited potent T-cell suppressive activity. Using the NeuMo gene signature, reanalysis of public scRNA-seq datasets identified a transcriptionally similar monocyte subset in chemotherapy-treated cancer patients. Collectively, our findings suggest that the expansion of NeuMo-like cells following chemotherapy represents a conserved immunoregulatory feedback mechanism with potential impact on tumor response to chemoimmunotherapy.

Chronic inflammation-driven bone loss in aging compromises bone regeneration and further impairs the bone-tendon interface (BTI). However, the cellular mechanisms by which inflammation exacerbates cellular senescence and consequently disrupts BTI healing remain unclear. Here, we identify M1 macrophage-mediated inflammation as a key driver of bone marrow-derived mesenchymal stem cells (BMSCs) senescence and bone microstructural deterioration. This senescence-associated decline in BMSCs ultimately compromises osteogenesis and delays BTI repair. To counteract these effects, we engineered a senomorphic and immunomodulatory platform by incorporating quercetin-primed senomorphic small extracellular vesicles (Sm-sEV) into a tissue-adhesive α-lipoic acid hydrogel (αLA-Gel) for sustained local delivery. The composite material modulates the inflammatory-senescent microenvironment by attenuating M1 macrophage-driven inflammation and enhancing BMSC resilience to inflammation-exacerbated senescence. Mechanistic analyses revealed that Sm-sEV/αLA-Gel suppresses cGAS-STING-NF-κB signaling, thereby reducing inflammation and improving BMSC resistance to senescence. In an osteoporotic rat rotator cuff repair model, Sm-sEV/αLA-Gel enhanced bone formation and fibrocartilage maturation, thereby promoting superior BTI integration and mechanical strength. Together, these findings identify inflammation-exacerbated BMSC senescence as a key pathological driver and demonstrate that dual regulation of inflammation and stem cell resilience enables robust regeneration of bone and the BTI under osteoporotic conditions.

Oxidative stress is increasingly recognized as a key contributor to the pathophysiology of periodontitis, particularly in patients with metabolic disturbances such as hyperlipidemia. The osteogenesis of periodontal ligament stem cells (PDLSCs) plays a pivotal role in maintaining alveolar bone homeostasis. In this study, we found that dysregulated lipid metabolism induces ferroptosis and mitochondrial dysfunction in PDLSCs, impairing their osteogenic differentiation and exacerbating alveolar bone loss in both in vitro and in vivo models. Mechanistically, free fatty acids activate glycogen synthase kinase 3 beta (GSK3β), which facilitates Kelch-like ECH-associated protein 1 (KEAP1)-independent, beta-transducin repeat-containing protein (β-TrCP)-mediated ubiquitin-proteasome degradation of nuclear factor erythroid 2-related factor 2 (NRF2). This leads to reduced expression of key antioxidant enzymes such as Glutathione peroxidase 4 (GPX4) and solute carrier family 7 member 11 (SLC7A11), resulting in redox imbalance and ferroptosis of PDLSCs. Notably, pharmacological inhibition of either GSK3β or ferroptosis restores NRF2 stability, alleviates oxidative stress, and rescues the osteogenic potential of PDLSCs. Furthermore, local inhibition of GSK3β significantly attenuates alveolar bone destruction in a hyperlipidemia-associated periodontitis mouse model. Collectively, our findings identify a novel GSK3β-NRF2-ferroptosis pathway that mediates the detrimental effects of hyperlipidemia on PDLSC function and periodontal homeostasis, offering a promising therapeutic target for metabolic disorder-associated periodontal damage.

Aplastic anemia (AA) is a bone marrow failure disease characterized by immune-mediated destruction of hematopoietic stem and progenitor cells. Bone marrow adiposity represents a typical pathological manifestation observed in AA.

The replenishment of specialized cells depends on the activity of stem cells. Recent advances in stem cell research have shown that the germline stem cells (GSCs) in Drosophila melanogaster can increase their mitotic activity in response to mating. Here, we show that this ability to respond to mating is eliminated if the males are mutant for either of the ABC transporters, White (W), Brown (Bw) or Scarlet (St), which are known for their role in eye pigmentation and amine production. However, reducing the expression of w specifically from the germline cells also caused a failure to increase GSC mitotic activity upon mating, suggesting that w is required intrinsically in the stem cells. The w gene is a common genetic background for genetic experiments and frequently used as a control. Our findings underline the importance of careful experimental design and control choice.

The IgG1-based bispecific antibody tobemstomig (RO7247669) simultaneously targets and blocks PD-1 and LAG-3 expressed on activated T cells.

John Gurdon was a towering figure in developmental biology, respected and admired throughout the world. His discovery, made when he was a PhD student, that the nuclei of differentiated cells retain their pluripotency was fundamental to stem cell research and regenerative medicine, and his career-long loyalty to Xenopus laevis as an experimental organism was a constant inspiration to the field. Although Xenopus has sometimes been written off as a model organism in favour of other species, it is probably true that we have learned more about early vertebrate development from its use than from that of any other species. John received many awards for his research, including the Nobel Prize in Physiology or Medicine, the Albert Lasker Basic Medical Research Award, and both the Copley Medal and the Royal Medal of the Royal Society. He was also a significant contributor to UK science infrastructure and to academic life more broadly. Not only did he co-found the institute that now bears his name, but he also served as a Governor of the Wellcome Trust, and of Eton College, as Master of Magdalene College, University of Cambridge, as President of the British Society for Cell Biology and as Chair of The Company of Biologists, the publisher of this journal. Few biologists in the UK have achieved so much or been so influential.

We previously developed an induced pluripotent stem cell-based model to study an intronic region of KCNQ1 that represents the strongest association signal with type 2 diabetes in Indigenous Americans from Arizona. The current study builds on this model by using CRISPR/Cas9-edited isogenic cells that differ only by targeted type 2 diabetes single nucleotide polymorphisms in this intronic region. The effect of KCNQ1 type 2 diabetes single nucleotide polymorphisms on pancreatic β-cell development and the probable mechanism of this effect were previously unknown. The current study shows an effect on INS and H19 gene expression dynamics specifically during the endocrine progenitor stage of pancreatic islet development likely via an epigenomic effect on gene regulation resulting in generation of lower β-like cells. Individuals carrying KCNQ1 risk alleles for type 2 diabetes will likely benefit from therapeutics that increase pancreatic β-cell mass.

Measurable residual disease (MRD) is a key prognostic factor for outcomes following allogeneic hematopoietic stem cell transplantation (allo-HSCT) in patients with acute myeloid leukemia. To enhance predictive performance, we developed a combined MRD assessment method that integrates the proportion of residual leukemic cells of ten-color multicolor flow cytometry (MFC) with peripheral blood WT1 mRNA expression.

Biomineralization refers to the process by which organisms form inorganic minerals, predominantly through the deposition of calcium phosphates. Calcium ions (Ca2+) serve not only as a fundamental component of the mineral phase but also as key signaling messengers that actively regulate the efficiency and progression of this process. The endoplasmic reticulum (ER) and mitochondria are two major organelles responsible for calcium ion storage and regulation within cells. Contact sites between mitochondria and ER, also called mitochondria-ER contacts (MERCs) or mitochondria-associated ER membranes (MAMs), have been identified as vital spots for calcium transfer. Existing research indicates that calcium ion transport from the ER to mitochondria occupies a pivotal position in biomineralization, but the relevance of MERC integrity in biomineralization is yet to be determined. This study revealed increased MERCs and calcium ion transport during mineralization in vivo and in vitro. Additionally, significantly impaired endoplasmic reticulum-mitochondrial interactions were observed in bone marrow mesenchymal stem cells (BMSCs) from ovariectomy-induced osteoporotic mice. Experimental enhancement of MERCs effectively increased mineralized nodule formation and alleviated ovariectomy-induced osteoporosis, whereas disruption of MERC integrity inhibited mineralization. Our findings indicate that endoplasmic reticulum-mitochondrial calcium ion transport plays a crucial role in biomineralization. This discovery provides a stronger theoretical foundation for elucidating the biomineralization process and may also identify novel therapeutic targets for related diseases.

The accuracy of crucial nuclear processes such as transcription, replication, and repair depends on the local composition of chromatin and the regulatory proteins that reside there. Understanding these DNA-protein interactions at the level of specific genomic loci has remained challenging due to technical limitations. Here, we introduce a method termed 'DNA O-MAP', which uses programmable peroxidase-conjugated oligonucleotide probes to biotinylate nearby proteins. We show that DNA O-MAP can be coupled with label-free or sample multiplexed quantitative proteomics, targeted chemical perturbations, and next-generation sequencing to quantify DNA-proximal proteins and DNA-DNA interactions at specific genomic loci in human and murine cells. Furthermore, we establish that DNA O-MAP is applicable to both repetitive and unique genomic loci of varying sizes, from kilobase HOX gene clusters to megabase alpha-satellite repeats, and that DNA O-MAP can measure proximal molecular effectors in a homolog-specific manner.

Normal mitochondrial function in stem cells is essential for effective bone regeneration, with mitochondrial complex IV (cytochrome c oxidase, CcO) playing a crucial role in sustaining electron transport chain activity and ATP synthesis. To address mitochondrial dysfunction associated with bone defects, we developed a dendritic mesoporous silica nanoparticle (DMSN)-based, CcO-mimetic nanozyme, named triphenylphosphonium (TPP)-DMSN-Fe/Cu. The nanozyme incorporated iron and copper single atoms to mimic the catalytic center of CcO and is modified with the mitochondria-targeting agent TPP. In vitro, TPP-DMSN-Fe/Cu nanozymes colocalized with mitochondria and enhanced mitochondrial function, effectively regulating cellular energy metabolism and promoting stem cell osteogenesis. In vivo, TPP-DMSN-Fe/Cu nanozymes resulted in significantly enhanced bone regeneration compared to the control, resulting in a 177% increase in bone volume and a 12% increase in mineral density at critical-sized bone defects in rats after 4 weeks of treatment. Taken together, these findings demonstrate that bioinspired, mitochondria-targeting TPP-DMSN-Fe/Cu nanozymes hold strong promise for accelerating bone regeneration via regulating cellular energy metabolism.

Extracellular vesicles (EVs) are promising vehicles for targeted therapeutic delivery, capable of encapsulating and transporting biomolecules to specific cells and tissues. Given that inflammation is central to many acute and chronic diseases, understanding EV biodistribution under inflammatory conditions is essential for therapeutic optimisation. This study examines how acute systemic inflammation influences EV biodistribution, clearance and plasma half-life, with a focus on the role of macrophages and their polarisation states. Using a lipopolysaccharide (LPS)-induced inflammation model in wild-type mice and bioluminescent and fluorescent labelling of EVs, we observed that inflammation extends the plasma half-life of EVs by over 600-fold within 2 h and 900-fold at 24 h post-administration, leading to significant enrichment in inflamed organs, particularly the liver and spleen. Enhanced accumulation in specific tissues translated to increased targeting of immune- and epithelial cells within those organs, with notable uptake by hepatocytes in the liver. To probe the mechanism, we profiled the EV protein corona, revealing inflammation-driven remodelling with enrichment of acute-phase proteins, complement factors and cytoskeletal regulators-linking corona composition to altered biodistribution. Yet, despite increased uptake and tissue accumulation, functional EV cargo delivery in vivo remained limited. These findings underscore the complex dynamics between EVs and immune cells under inflammatory conditions and provide critical insights for advancing EV-based therapies in chronic inflammatory diseases.

Advancements in tissue engineering have revolutionized therapeutic paradigms for diabetic tissue defects; however, the lack of applicable scaffold containing various bioactive substance aggregates remained a critical bottleneck hindering satisfactory repair effect. In this study, adipose-derived stem cells (ADSCs) were functionally re-engineered using lipoic acid (LA) to fabricate a novel LA-intervened stem cell spheroid (LA-SCS) with enhanced paracrine activity and extracellular matrix (ECM) biosynthetic capacity. Subsequent decellularization mitigated immunogenicity, yielding LA-intervened decellularized stem cell spheroid (LA-dSCS). In vitro assays confirmed its immunomodulatory potency, as evidenced by the activation of signaling cascades associated with macrophage reprogramming, homeostasis, and autophagy. Furthermore, leveraging the intrinsic viscoelastic properties of the LA-dSCS, a convenient preparation method for preparing LA-dSCS derived injectable material was established, wherein LA-dSCS micro-particles assemble into LA-dSCS granular gel. In vivo studies using diabetic rat models demonstrated closure of both wound and cranial defects. Collectively, this study established a biomimetic engineering strategy that integrates cell-free bioactive aggregates with injectable granular gels, offering a novel proof‑of‑concept strategy for the regeneration of complex diabetic tissue defects.

Regenerative repair of segmental bone defect remains a major clinical challenge. The conventional mental implants suffer from mechanical strength mismatch and long-term foreign bodies presence. While, the osteoinductive materials lack insufficient mechanical strength for the repair of load-bearing bone. Inspired by bamboo, whisker-reinforced Ca-P ceramics (HW) have been developed to accelerate segmental bone regeneration. Bamboo-like whiskers can reduce the stress concentration and impede crack propagation via whisker broken, whisker bridging, and crack deflection, achieving 3 times increase in the compressive strength compared to traditional ceramics. In addition, HW significantly promotes the formation of type-H endothelial cells (ECs) via the integrin-mediated HIF-1 signaling pathway, which can secrete coupling factors (e.g. Noggin), to promote the osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs). In turn, HW can stimulate BMSCs to secrete coupling factors (e.g. VEGF) to support angiogenesis. In the segmental bone defect model, DFO is introduced to bamboo-like whiskers (HW+DFO) to enhance type-H vessels formation. HW+DFO can effectively promote the repair of segmental bone defects with mechanical recovery reaching 40% of that of normal femur. In conclusion, this study proposes a novel strategy for promoting bone regeneration by regulating type-H vessels, offering a potential solution for addressing segmental bone defects.