Disease Models & Mechanisms最新文献

{"title":"Single-cell atlas of neuroma-induced DRG remodeling reveals intervention-specific glial and immune programs.","authors":"Casey L Stewart, Michael M Morris, Alexandra E Halevi, Amy M Moore, Valeria Cavalli, Oshri Avraham","doi":"10.1242/dmm.053052","DOIUrl":"https://doi.org/10.1242/dmm.053052","url":null,"abstract":"<p><p>Peripheral nerve injury caused by cut, crush, or excessive stretch can lead to disordered regeneration and painful neuroma formation. Regrowing axons may terminate in a swollen, hypersensitive nerve stump, producing pain that can outweigh sensory or motor deficits. Despite the frequency of neuromas, treatment outcomes remain inconsistent, and the mechanisms that initiate and sustain neuroma-associated pain are poorly understood. A proximal nerve crush performed upstream of a neuroma or transection may reshape axonal growth and interrupt retrograde injury signaling, potentially promoting a regenerative, pain-resolving state. However, its long-term effects on dorsal root ganglion (DRG) programs remain unclear. Here, we use single-cell RNA sequencing to build an atlas of DRG remodeling after neuroma-forming injury and compare it with two interventions: proximal nerve crush and nerve resection. By resolving transcriptional responses across sensory neurons, satellite glial cells, Schwann cells, and macrophages, we identify intervention-specific glial, neuronal, and immune programs that distinguish regenerative from persistent injury-associated states and nominate pathways that may guide mechanism-based therapies for painful neuromas.</p>","PeriodicalId":11144,"journal":{"name":"Disease Models & Mechanisms","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2026-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149220031","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Comprehensive cardiac, vascular, and pulmonary characterization of a cardiometabolic HFpEF model.","authors":"Ibrahim Aykac, Christoph A Baumgartner, Ouafa Hamza, Attila Kiss, Bruno K Podesser","doi":"10.1242/dmm.053163","DOIUrl":"https://doi.org/10.1242/dmm.053163","url":null,"abstract":"<p><strong>Background: </strong>Heart failure with preserved ejection fraction (HFpEF) is a heterogeneous syndrome in which translational progress is limited by experimental models that insufficiently reflect the cardiometabolic phenotype while affecting endogenous endothelial function. We aimed to characterize a cardiometabolic \"two-hit\" HFpEF model combining metabolic stress (db/db) with chronic mineralocorticoid excess (d-aldosterone), focusing on integrated cardiac, vascular, and pulmonary phenotyping.</p><p><strong>Methods: </strong>Female db/db mice received 4-week d-aldosterone (0.3 µg/h) or vehicle via osmotic minipumps. Metabolic profiling, high-resolution echocardiography including strain and left atrial mechanics, invasive right-heart catheterization, and thoracic aortic wire myography were performed.</p><p><strong>Results: </strong>Aldosterone-treated db/db mice developed cardiac hypertrophy and pulmonary congestion with preserved LVEF but marked diastolic dysfunction, left atrial remodeling with increased stiffness, and impaired global longitudinal LV strain. Pulmonary hypertension with right ventricular dysfunction was evidenced by elevated RVSP/estimated mPAP, reduced PAT/PET, and reduced TAPSE. Thoracic aortae from untreated db/db mice already showed impaired endothelium-dependent relaxation, which was further aggravated by aldosterone, whereas maximal endothelium-independent relaxation remained largely preserved.</p><p><strong>Conclusions: </strong>The db/db+d-aldosterone model recapitulates key features of cardiometabolic HFpEF across the cardiac-vascular-pulmonary axis and provides a translational platform for mechanistic and therapeutic studies targeting endothelial and ventricular-vascular dysfunction in HFpEF. New & Noteworthy: Current HFpEF animal models often limit the investigation of vascular dysfunction, a central component of cardiometabolic HFpEF. We provide a comprehensive functional characterization of a db/db+d-aldosterone two-hit model demonstrating obesity, diabetes, diastolic dysfunction, atrial remodeling, endothelial dysfunction, pulmonary hypertension, and right ventricular impairment. By preserving endogenous endothelial nitric oxide signaling, this model offers a translational platform for studying vascular and cardiopulmonary mechanisms in cardiometabolic HFpEF.</p>","PeriodicalId":11144,"journal":{"name":"Disease Models & Mechanisms","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2026-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149220019","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Distinct biological and biomechanical features in jaw and knee cartilage contribute to their degenerative susceptibility.","authors":"Jingyu He, Hong Colleen Feng, Junxi Guo, Julia Raulino Lima, Mohammadreza Vatankhah, Fangzhou Bian, Holly Katherine Johnson, Courtney Leong, Laura Voskanyan, Jantzen Blaine Ebreo, Parth Kotak, Glenn Thomas Clark, Anette Vistoso Monreal, Amy E Merrill, Jian-Fu Chen, Jian Xu, Zhaoyang Liu","doi":"10.1242/dmm.052994","DOIUrl":"10.1242/dmm.052994","url":null,"abstract":"<p><p>The temporomandibular joint (TMJ) and knee joint are both prone to degenerative diseases such as osteoarthritis (OA); however, TMJ-OA generally manifests earlier than knee OA, with underlying mechanisms largely unknown. In this study, we explored potential explanations through comprehensive biological and biomechanical analyses in mice. Structurally, the mandibular condylar cartilage (MCC) exhibits prominent differences from tibial articular cartilage (AC) at occlusion establishment, evidenced by distinct extracellular matrix organization and enriched transcription factor expression toward the posterior TMJ. Both jaw and knee cartilage house progenitor-like, slow-cycling cells at the cartilage surface, but these cells are depleted more rapidly in the MCC, associated with faster tissue turnover and cellular replenishment. Biomechanically, the MCC exhibits a lower elastic modulus (EIT) than the tibial AC. This biomechanical feature is correlated with its unique extracellular matrix composition to support the force-bearing jaw movement at the anterior TMJ, while providing cushioning and compliance to protect a putative stem/progenitor cell niche at the posterior TMJ. Together, these findings highlight fundamental biological and biomechanical distinctions between jaw and knee cartilage that may underlie their different susceptibility to degeneration.</p>","PeriodicalId":11144,"journal":{"name":"Disease Models & Mechanisms","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2026-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149135354","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Loss of transcriptional factor Zbtb33 fails to induce clonal hematopoiesis in mice but plays a role in tumor growth.","authors":"Yuhang Li, Kaiping Luo, Keyao Xia, Jingjing Liu, Zhigang Zhao, Zhigang Cai, Ge Dong","doi":"10.1242/dmm.052484","DOIUrl":"https://doi.org/10.1242/dmm.052484","url":null,"abstract":"<p><p>Clonal hematopoiesis (CH) is an early indicator of hematologic malignancies, driven by mutations in hematopoietic stem cells (HSCs) such as TET2 or P53. Recently ZBTB33 mutations have been implicated in myelodysplastic syndromes (MDS) and suggested as a driver of CH. However, the role of ZBTB33 in hematopoiesis and its causative involvement in CH remains unclear. We generated a Zbtb33-knockout mouse strain to elucidate its function in hematopoiesis and tumor growth. Our findings indicate that hematopoiesis in Zbtb33-knockout mice appeared grossly normal, and competitive bone marrow transplantation assays demonstrated that loss of Zbtb33 in HSCs did not confer expansional advantage. Introducing Zbtb33-mutation into Tet2- or P53-mutation background yielded no synergistical effects. Nevertheless, tumor-bearing experiments revealed that hematopoietic loss of Zbtb33 accelerated solid tumor growth. In summary, Zbtb33 knockout was insufficient to induce clonal hematopoiesis in mice but may play a role in tumor growth through the hematopoietic compartment.</p>","PeriodicalId":11144,"journal":{"name":"Disease Models & Mechanisms","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2026-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149105494","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pharmacokinetics and efficacy of tank-water-administered dabrafenib, a BRAF inhibitor, in a zebrafish model of melanoma.","authors":"Jenna Villman, Nikol Dibus, Jonas Huhn, Anna-Mari Haapanen-Saaristo, Ilia Evstafev, Alex M Dickens, Oliver Scherf-Clavel, Ilkka Paatero, Kari J Kurppa","doi":"10.1242/dmm.052907","DOIUrl":"10.1242/dmm.052907","url":null,"abstract":"<p><p>Zebrafish models are widely used to study BRAF-mutant melanoma biology. However, long-term treatment of adult fish with small-molecule BRAF inhibitors remains challenging, and pharmacokinetic data to inform rational dosing strategies are largely lacking for most small molecules in zebrafish. Here, we assessed the pharmacokinetics, metabolism and efficacy of continuously tank-water-administered dabrafenib, a BRAF inhibitor, in adult zebrafish. Dabrafenib was rapidly absorbed from tank water, reaching efficacious plasma levels within 1 h, but also showed fast elimination kinetics with a half-life of 1.0 h. Most human metabolites of dabrafenib were detected in zebrafish, suggesting conserved metabolic processes. Continuous tank-water administration achieved therapeutically relevant steady-state dabrafenib plasma levels that inhibited BRAF-driven signaling and produced robust efficacy in vivo in a genetic zebrafish model of BRAF-mutant melanoma without apparent toxicity. Together, these results demonstrate that continuous tank-water administration of dabrafenib is a feasible, efficient and well-tolerated dosing strategy in zebrafish melanoma models, and may facilitate dosing of other small-molecule inhibitors, especially those with a short in vivo half-life in zebrafish.</p>","PeriodicalId":11144,"journal":{"name":"Disease Models & Mechanisms","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148963349","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dysregulated microRNA-mRNA networks in SOD1G93A skeletal muscle reveal metabolic impairments in amyotrophic lateral sclerosis.","authors":"Libby Moody, Eleni Christoforidou, Greig Joilin, Andrew Dilley, Majid Hafezparast","doi":"10.1242/dmm.052963","DOIUrl":"10.1242/dmm.052963","url":null,"abstract":"<p><p>Amyotrophic lateral sclerosis (ALS) is a multi-system disease in which skeletal muscle actively contributes to pathology, yet the regulatory circuits that drive muscle dysfunction remain unclear. We examined miRNA-mRNA interactions in the gastrocnemius of hSOD1G93A mice across pre-, early- and late-symptomatic stages, using RNA sequencing, bioinformatics and reverse transcription quantitative PCR (RT-qPCR). Compared with hSOD1WT and non-transgenic control muscle, hSOD1G93A muscle showed mutation-specific transcriptome reprogramming: 48 dysregulated miRNAs and 558 mRNAs at pre-symptomatic, and 64 miRNAs and 685 mRNAs at late-symptomatic, stages. Functional enrichment pinpointed carbohydrate-handling pathways (glycolysis/gluconeogenesis, pentose-phosphate, fructose-mannose metabolism) as the dominant downregulated gene sets. Network analysis revealed clusters in which upregulated miRNAs converged on, and showed inverse expression patterns relative to metabolic transcripts. RT-qPCR confirmed inverse expression of ten candidate miRNAs and 11 metabolic mRNAs, substantiating miRNA-guided repression of glycolytic enzymes and energy-sensing nodes. Collectively, we show that SOD1G93A drives an early, sustained miRNA signature that dampens glycolysis gene expression, which could promote the fast-to-slow fibre-type transition and exacerbate energy deficit in ALS muscle. Targeting these circuits offers a strategy to restore metabolic balance and slow disease progression.</p>","PeriodicalId":11144,"journal":{"name":"Disease Models & Mechanisms","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148918781","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A patient-derived missense mouse model of Kabuki syndrome 1.","authors":"Sara Tholl Halldorsdottir, Meghna Vinod, Hilmar Orn Gunnlaugsson, Ellen Dagmar Bjornsdottir, Romain Maurice Jacques Lasseur, Teresa Luperchio, Jill A Fahrner, Agnes Ulfig, Hans Tomas Bjornsson","doi":"10.1242/dmm.052775","DOIUrl":"10.1242/dmm.052775","url":null,"abstract":"<p><p>Kabuki syndrome type 1 (KS1) is a rare cause of intellectual disability resulting from heterozygous pathogenic variants in the gene encoding the histone methyltransferase KMT2D. A previously established loss-of-function mouse model of KS1 exhibits key phenotypic features, and therapeutic trials in this mouse model suggest postnatal malleability of neurological symptoms. However, 15-30% of individuals with KS1 carry missense variants. To investigate whether missense variants lead to similar phenotypic presentation in mice, we used CRISPR-Cas9 to introduce the KS1 patient variant R5179H, corresponding to R5230H in mice, into C57BL/6NTac animals. Computational and in vitro testing suggested that the R5230H variant does not impair protein stability or enzyme function of KMT2D. Despite a distinct mechanistic basis, our new mouse model (Kmt2d+/R5230H) recapitulated most phenotypes of our prior loss-of-function model, including growth deficiency, craniofacial anomalies and IgA deficiency, but not altered neurological function. Kmt2d+/R5230H mice showed perinatal lethality and a high frequency of unilateral kidney agenesis, a novel phenotype in KS1 mouse models. Kmt2d+/R5230H mice provide a unique opportunity to understand the impact of missense variants on KMT2D function and uncover developmental and perinatal abnormalities in KS1.</p>","PeriodicalId":11144,"journal":{"name":"Disease Models & Mechanisms","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148911172","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cognitive flexibility deficits differ between the sexes in a transchromosomic mouse model of Down syndrome.","authors":"Elysabeth Otte, Nicole Gordon, Andrew Folz, Charles Goodlett, Randall Roper","doi":"10.1242/dmm.053030","DOIUrl":"https://doi.org/10.1242/dmm.053030","url":null,"abstract":"<p><p>Individuals with Down syndrome (DS) exhibit cognitive and behavioral phenotypes, including intellectual disability, and reduced cognitive flexibility. The TcMAC21 DS mouse model (Tc(HSA21,CAG-EGFP)1Yakaz/J) has a freely segregating human chromosome 21 containing ∼93% of protein-coding genes and was hypothesized to show significant deficits in behavioral, learning, and memory tests. Examination of male and female TcMAC21 and control mice from postnatal day (P) 45-P62 showed TcMAC21 mice had lower body weight, with greater differences in males. Locomotor activity testing on P45 revealed TcMAC21 mice had greater activity than controls early in the session and increased time in the arena center later in the session, and a longer stride length in gait analysis. In the Morris water maze, TcMAC21 mice did not differ significantly from euploid littermates on acquisition of either cued or place training, though male (but not female) TcMAC21 mice showed significant deficits during reversal, providing the first demonstration of sex-specific impairment of cognitive flexibility in DS mouse models. These findings support the hypothesis that in young adults with DS, males may exhibit more severe deficits in cognitive flexibility than females.</p>","PeriodicalId":11144,"journal":{"name":"Disease Models & Mechanisms","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2026-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149001448","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mitochondrial defects in the cAMP-PKA-DRP1 pathway in a Crppa deletion model of dystroglycanopathy.","authors":"Jihang Luo, Yidan Liu, Danyu Song, Shiqi Yang, Xiaona Fu, Lin Ge, Cuijie Wei, Liya Cui, Yanwei He, Jin Xu, Qiang Shen, Yuxuan Guo, Motoi Kanagawa, Tatsushi Toda, Jingmin Wang, Hong Zhang, Hui Xiong","doi":"10.1242/dmm.052890","DOIUrl":"10.1242/dmm.052890","url":null,"abstract":"<p><p>Dystroglycanopathies (DGPs) are autosomal recessive muscular dystrophies caused by abnormal α-dystroglycan glycosylation. CRPPA is one causative gene, with deletion of exons 6-9 identified as a founder variant in Chinese patients. Our previous study revealed mitochondrial abnormalities in patient muscle biopsies, although the underlying mechanism(s) remained unclear. A Crppa knockout mouse (dyC/dyC) was generated based on the founder variant, displaying muscle weakness, cerebellar hypoplasia, retinal abnormalities and neonatal lethality within 24 h. Electron microscopy showed mitochondrial structural defects in skeletal muscle, consistent with patient findings. RNA sequencing revealed dysregulation of the cAMP-PKA pathway, accompanied by decreased ATP and reduced phosphorylation of PKA and DRP1 (Ser637). To verify the link between CRPPA deficiency and mitochondrial dysfunction, Crppa knockdown C2C12 cells and CRPPA-related DGP patient-derived fibroblasts were examined. Both models exhibited reduced DRP1 Ser637 phosphorylation and ATP levels. Treatment with cAMP-PKA activators restored DRP1 phosphorylation and ATP production in a time-dependent manner. Recovery of mitochondrial membrane potential was confirmed by JC-1 staining. These findings suggest that CRPPA deficiency is associated with mitochondrial dysfunction involving the cAMP-PKA-DRP1 axis, suggesting a candidate pathway warranting further investigation for DGPs.</p>","PeriodicalId":11144,"journal":{"name":"Disease Models & Mechanisms","volume":"19 9","pages":""},"PeriodicalIF":3.6,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13617977/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148988691","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Preserved satellite cell pool in a laminin-α2-deficient model of congenital muscular dystrophy.","authors":"Luiza Albuquerque Coelho, Antônio Fernando Ribeiro Junior, Letícia Nogueira Feitosa, Felipe Tadeu Galante Rocha de Vasconcelos, Job Carvalho Bezerra, Mariz Vainzof","doi":"10.1242/dmm.052782","DOIUrl":"10.1242/dmm.052782","url":null,"abstract":"<p><p>Deficiency in the α2 subunit of laminin-211, encoded by LAMA2, causes congenital LAMA2-related muscular dystrophy (LAMA2 MD), characterized by severe and progressive muscle weakness. In this study, we analyzed muscle regeneration and degeneration in the gastrocnemius muscle of dy2J mice, a model of LAMA2 MD, across different ages. We found that the proportion of satellite cells (SCs) per fiber was significantly higher in the dy2J groups compared to that in the wild-type (WT) group, and that SC numbers did not decrease with disease progression. The percentages of activated SCs, and the expression of Myog and Tgfb, were also significantly elevated in affected animals compared to those in WT animals. Despite the preserved SC pool and their activation, the percentage and diameter of newly regenerated fibers progressively declined as the disease advanced. Histopathological analysis further revealed progressive fiber muscle atrophy. These results suggest that the impairment of muscle regeneration with time in the dy2J model is not due to SC depletion but rather a failure at the later stages of SC differentiation. Further investigation into these processes is essential for developing effective treatment strategies for LAMA2 MD.</p>","PeriodicalId":11144,"journal":{"name":"Disease Models & Mechanisms","volume":"19 9","pages":""},"PeriodicalIF":3.6,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13670365/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149080071","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}