Alterations in synaptic homeostasis are linked to cognitive and behavioural impairments in brain disorders. However, synaptic dysfunction in childhood dementia is poorly understood. Here, we generate human cortical circuits from induced pluripotent stem cells (iPSCs) derived from donors with Mucopolysaccharidosis Type IIIA (MPS IIIA), also known as Sanfilippo syndrome, a common form of childhood-onset dementia. Action potential firing capacity and morphology of MPS IIIA patient neurons in culture are similar to those of neurons from neurotypical donors. However, long-term neural maturation reveals excitation/inhibition imbalances caused by hyperactive excitatory synapses, disrupted network dynamics, and dysregulated gene expression linked to synaptic homeostasis. This study validates in vitro human neural models to detect neurophysiological phenotypes in childhood dementias and supports drug discovery strategies that target synaptic dysfunction to improve cognition in MPS IIIA and related brain disorders.

Intestinal epithelium relies on intestinal stem cells (ISCs) for rapid and precise tissue replenishment to maintain gut normal function. The self-renewal maintenance of ISCs is finely regulated by multiple stemness factors and signaling pathways. However, the transcription mechanisms of some key stemness factors remain poorly understood. Here, we identify that small nucleolar RNA Snora61 is highly expressed in ISCs. Snora61 is mainly distributed in the nucleoplasm. Snora61 knockout impairs ISC self-renewal and intestinal regeneration. Mechanistically, Snora61 binds to the promoter region of Lgr5 gene and engages with RNA-binding protein RBMX to recruit HMGB2 onto Lgr5 promoter, leading to Lgr5 transcription and expression. Snora61 promotes the self-renewal of small intestinal stem cells, which in turn enhances the proliferation of differentiated epithelial cells, thereby contributing to the maintenance of intestinal homeostasis. Conversely, Snora61 knockout causes reduced LGR5 expression. Deletion of Lgr5 with Snora61 displays more severely impaired ISC self-renewal and intestinal regeneration. Our findings reveal a regulatory mechanism of Lgr5 transcription underlying ISC self-renewal maintenance.

CD8+ T stem cell memory (TSCM) cells show clinical promise for cancer immunotherapy, but TSCM cell generation in clinical settings requires further optimization. Ponatinib is a tyrosine kinase inhibitor primarily targeting BCR-ABL1 and used for the treatment of chronic myeloid leukemia. Here, we investigate the effect of ponatinib on T cell activation and differentiation. Acting off-target, ponatinib inhibits LCK and PI3K signaling to enhance the transcriptional functions of TCF7 and FOXO1, thereby promoting CD8+ TSCM cell differentiation. Mechanistically, stable and sustained, but not intermittent, inhibition of the LCK and PI3K pathways is essential for CD8+ TSCM cell induction. In mouse tumor models, ponatinib treatment exhibits antitumor efficacy alone and in combination with PD-1 blockade. Furthermore, ponatinib increases chimeric antigen receptor (CAR) TSCM cells by reducing CAR T cell exhaustion, resulting in durable antitumor efficacy. Our results thus implicate ponatinib as therapeutic immunomodulator, inducing TSCM cells for improved antitumor T cell activity.

Male infertility is closely related to DNA double-strand breaks in spermatogonial stem cells (SSCs); however, the precise mechanism still remains to be fully elucidated. While SIRT1 is a key regulator of DNA damage response and cellular senescence in other contexts, its role in SSCs is still poorly understood. In this study, human testicular single-cell RNA sequencing datasets were reanalyzed to characterize SSC transcriptional programs in non-obstructive azoospermia (NOA) patients. Clinical validation was performed on testicular sections from obstructive azoospermia controls and NOA patients. X-ray irradiation and hydroxyurea-based DNA damage models were applied to interrogate SSC DNA damage responses in vivo and in vitro. Immunofluorescence, western blotting, co-immunoprecipitation, growth and survival assays, flow cytometry, a GFP-based NHEJ reporter, and acetylation analyses were used to define SIRT1-associated pathways. Single-cell analysis revealed an overall attenuation of NHEJ-related signatures and reduced SIRT1 expression in SSCs from NOA compared with controls. In clinical specimens, confocal immunofluorescence confirmed a reduced SSC pool and decreased SIRT1 and 53BP1 signals within PLZF-positive SSCs, while KU70 levels were not significantly changed. In experimental models, acute DNA damage induced a rapid SIRT1 response in SSCs. Functional assays showed that SIRT1 supports SSC homeostasis by promoting proliferative capacity and influencing apoptosis and survival under hydroxyurea-induced DNA damage. Mechanistically, SIRT1 co-localized and physically interacted with KU70, with enhanced association under genotoxic stress. NHEJ reporter assays showed reduced repair efficiency following Sirt1 knockdown. Moreover, Sirt1 overexpression may down-regulate KU70 acetylation, indicating a deacetylation-dependent mechanism in NHEJ regulation. Collectively, these findings identify SIRT1 as a stress-responsive regulator of SSC genome maintenance that functionally cooperates with KU70 to support NHEJ-associated repair and limit DNA damage-driven SSC loss. The SIRT1-KU70 axis represents a potential target to mitigate genotoxic injury-associated germline stem cell attrition and preserve male fertility.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by amyloid-β (Aβ) accumulation, tau hyperphosphorylation, neuroinflammation, and synaptic loss. Existing therapies provide only modest symptomatic relief and fail to slow disease progression. Beyond its role in promoting pituitary growth hormone (GH) secretion, growth hormone-releasing hormone (GHRH) has shown neuroprotective effects in experimental ischemic stroke and spinal muscular atrophy. Here, we explored the therapeutic potential of GHRH and its agonist MR-409 in AD models. In vitro, GHRH(1-44)NH₂ promoted survival, proliferation, and neuronal differentiation of rat hippocampal neural stem cells (NSCs) and human SH-SY5Y neuroblastoma cells under growth factor deprivation and amyloid beta (Aβ)1-42 exposure. These effects involved the cAMP/PKA/CREB, ERK1/2, and PI3K/Akt signaling pathways. GHRH also attenuated Aβ-induced neurotoxicity by reducing apoptosis, suppressing GSK-3β activity and tau phosphorylation, restoring nuclear β-catenin, and inhibiting NF-κB-mediated inflammation. In vivo, subcutaneous administration of MR-409 in 5xFAD mice reduced Aβ deposition, tau phosphorylation, gliosis, and proinflammatory cytokine expression. In addition, MR-409 mitigated neuronal and synaptic loss, activated survival and neurogenic pathways, and improved cognitive performance, without altering systemic GH and IGF1 levels. MR-409 also elevated NRF2 mRNA expression while reducing its negative regulator KEAP1. Overall, these findings indicate that GHRH and its analog MR-409 exert neuroprotective effects by modulating key pathological features of AD, including neurodegeneration, impaired neurogenesis, neuroinflammation, and oxidative stress. Given their ability to modulate multiple pathological pathways, GHRH agonists may represent promising therapeutic candidates for AD and other neurodegenerative disorders.

Insufficient skeletal repair is the primary threat of health span and lifespan in elders with increasingly vast global burden; yet, to date, the knowledge of resolving this crisis remains limited. In this study, we addressed the specific mechanisms underlying aging-associated poor bone repair, which are driven by the mitochondrial DNA structures mitochondrial G-quadruplex (mtG4). We found that mtG4 is spatiotemporal-wisely accumulated within Pdgfra+ periosteal mesenchymal stromal/stem cells (PPM) both in healthy and premature aging, which substantially increases cellular senescence and the degenerative alterations of PPM. By utilizing transgenic lineage tracking, PPM organoids formation, mitochondrial transgenic mutation, organoids transplantation, and serial cellular molecular investigations, we reveal that mtG4 in PPM restricts vital mitochondrial genes' transcription to cause mitochondrial dysfunction, which utterly leads to severe mitophagy and cell senescence. These senescent PPM demonstrates impaired stemness and disrupted fate determination, finally phenocopying aging-associated poor bone repair. This study decodes the mitochondrial genomic reasons for insufficient bone repair during aging, which offers insights for developing cell-type- and disease-specific senolytic therapies in the future.

Effective pharmacological therapies for small abdominal aortic aneurysms (AAAs) remain lacking. Most preclinical work focuses on aneurysm initiation rather than treatment of established disease, reducing translational relevance.

The lymphatic vasculature maintains tissue fluid homeostasis, lipid transport, and immune surveillance. Beyond these classical roles, lymphatic vessels regulate tissue development and repair through lymphangiocrine signalling, whereby lymphatic endothelial cells (LECs) secrete mediators such as Reelin, R-spondin-3, and CCL21 that modulate stem cell niches, immune trafficking, and regeneration. Ageing-associated lymphatic dysfunction, driven by LEC senescence, impaired lymphangiogenesis, and lymph node stromal remodelling, leads to defective tissue repair, chronic low-grade inflammation, and increased susceptibility to diseases including cancer, cardiovascular disease, and neurodegeneration.

The neuromuscular disorder myotonic dystrophy Type 1 (DM1) is brought on by CTG trinucleotide repeat expansions in the dystrophia myotonica-protein kinase (DMPK) gene, which leads to progressive myotonia and muscle weakness. We used Sendai virus reprogramming to generate two induced pluripotent stem cell (iPSC) lines (SCVIi134-A and SCVIi137-A) from peripheral blood mononuclear cells (PBMCs) of female DM1 patients carrying CTG repeat expansion. Both lines have normal karyotypes, show expression of undifferentiated human iPSC state markers, and differentiate into all three germ layers. These iPSC lines provide a platform for studying RNA toxicity at the molecular level and for drug development.

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.