EMBO Molecular Medicine最新文献_第3页

Oncolytic viruses expressing MATEs facilitate target-independent T-cell activation in tumors. 表达MATEs的溶瘤病毒促进肿瘤中不依赖靶标的t细胞活化。

IF 9 1区医学

EMBO Molecular Medicine Pub Date : 2025-02-01 Epub Date: 2025-01-09 DOI: 10.1038/s44321-024-00187-y

Malin Peter, Bettina Mundt, Arne Menze, Norman Woller, Valery Volk, Amanda M Ernst, Leon A Öhler, Steven R Talbot, Heiner Wedemeyer, Christine Falk, Friedrich Feuerhake, Thomas C Wirth, Florian Kühnel

{"title":"Oncolytic viruses expressing MATEs facilitate target-independent T-cell activation in tumors.","authors":"Malin Peter, Bettina Mundt, Arne Menze, Norman Woller, Valery Volk, Amanda M Ernst, Leon A Öhler, Steven R Talbot, Heiner Wedemeyer, Christine Falk, Friedrich Feuerhake, Thomas C Wirth, Florian Kühnel","doi":"10.1038/s44321-024-00187-y","DOIUrl":"10.1038/s44321-024-00187-y","url":null,"abstract":"Oncolytic viruses (OV) expressing bispecific T-cell engagers (BiTEs) are promising tools for tumor immunotherapy but the range of target tumors is limited. To facilitate effective T-cell stimulation with broad-range applicability, we established membrane-associated T-cell engagers (MATEs) harboring the protein transduction domain of the HIV-Tat protein to achieve non-selective binding to target cells. In vitro, MATEs effectively activated murine T cells and improved killing of MC38 colon carcinoma cells. Similarly, humanized MATEs activated T cells in PBMCs from human donors. In MC38-tumors in mice, MATE-expression by the oncolytic adenovirus Ad5/11 facilitated intratumoral T-cell activation, reduced tumor growth and prolonged survival accompanied by infiltration of tumor-directed CD8+ T cells and improved CD8/CD4 T-cell ratio. Absence of early T-cell activation in tumor draining lymph nodes suggests the safe applicability of this strategy. Furthermore, MATE-expression by Ad5/11 was capable of breaking resistance to αPD-1 checkpoint therapy thereby promoting T-cell/tumor cell proximity and clustering of CD8+ and CD4+ T cells. In summary, we demonstrated that MATE expressing OVs are powerful T-cell activating tools suitable for local immunotherapy of a broad range of tumors.","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":" ","pages":"265-300"},"PeriodicalIF":9.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11821991/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142946571","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

CAR T-cell-associated secondary malignancies challenge current pharmacovigilance concepts.

IF 9 1区医学

EMBO Molecular Medicine Pub Date : 2025-02-01 Epub Date: 2025-01-06 DOI: 10.1038/s44321-024-00183-2

Philipp Berg, Gabriele Ruppert-Seipp, Susanne Müller, Gabriele D Maurer, Jessica Hartmann, Udo Holtick, Christian J Buchholz, Markus B Funk

{"title":"CAR T-cell-associated secondary malignancies challenge current pharmacovigilance concepts.","authors":"Philipp Berg, Gabriele Ruppert-Seipp, Susanne Müller, Gabriele D Maurer, Jessica Hartmann, Udo Holtick, Christian J Buchholz, Markus B Funk","doi":"10.1038/s44321-024-00183-2","DOIUrl":"10.1038/s44321-024-00183-2","url":null,"abstract":"Suspected adverse reactions following chimeric antigen receptor T-cell (CAR T) treatment include more and more cases of secondary T-cell malignancies. The causality assessment of such suspected reactions challenges established evaluation practices due to (i) patient and product-specific risk factors and (ii) incomplete data available with post-marketing reports submitted to competent authorities. This is of particular relevance for gene therapy products that integrate into the host genome. We present a summary of case reports related to different CAR T products and the rationale for case causality assessment. In this context, possible pathophysiologic mechanisms and differences between CAR T products to be taken into account are discussed. The unparalleled complexity of the case follow-up and the multistep process of cancer development necessitates a case-by-case consideration. This highlights challenges in the pharmacovigilance of advanced therapy medicinal products and underlines the importance of testing for vector presence, integration location and gene expression profile for an informed case assessment of suspected secondary malignancies with the aim to obtain a better understanding of contributing factors.","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":"17 2","pages":"211-218"},"PeriodicalIF":9.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11822130/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143406504","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

A therapeutic regimen using neoantigen-specific TCR-T cells for HLA-A*2402-positive solid tumors. 新抗原特异性TCR-T细胞治疗HLA-A*2402阳性实体瘤的治疗方案

IF 9 1区医学

EMBO Molecular Medicine Pub Date : 2025-02-01 Epub Date: 2025-01-02 DOI: 10.1038/s44321-024-00184-1

Yuncheng Bei, Ying Huang, Nandie Wu, Yishan Li, Ruihan Xu, Baorui Liu, Rutian Li

{"title":"A therapeutic regimen using neoantigen-specific TCR-T cells for HLA-A*2402-positive solid tumors.","authors":"Yuncheng Bei, Ying Huang, Nandie Wu, Yishan Li, Ruihan Xu, Baorui Liu, Rutian Li","doi":"10.1038/s44321-024-00184-1","DOIUrl":"10.1038/s44321-024-00184-1","url":null,"abstract":"The adoptive transfer of TCR-T cells specific to neoantigens preferentially exhibits potent cytotoxicity to tumor cells and has shown promising efficacy in various preclinical human cancers. In this study, we first identified a functional TCR, Tcr-1, which selectively recognized the SYT-SSX fusion neoantigen shared by most synovial sarcomas. Engineered T-cell expressing Tcr-1 (Tcr-T1) demonstrated HLA-A*2402-restricted, antigen-specific anti-tumoral efficacy against synovial sarcoma cells, both in vitro and in vivo. Furthermore, to extend its application, we developed a cooperative therapeutic modality, in which exogenous SYT-SSX fusion neoantigen was loaded into stimuli-responsive nanoparticles (NPs) formed by mPEG-PVGLIG-PCL copolymers (Neo-AgNPs) for tumor targeting delivery. As expected, Neo-AgNPs were proven to have great tumor penetration and local release. In situ, the modification was able to direct engineered Tcr-T1 against other HLA-A*2402-positive malignant cancer cell lines with significant antigen-specific cytotoxicity despite their inherent mutation profiles. With these favorable data, our established cooperative therapeutic modality has great potential for further clinical investigation and provides new insight for future TCR-T cell therapy development.","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":" ","pages":"365-383"},"PeriodicalIF":9.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11821884/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142920815","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Microbial metabolites tune amygdala neuronal hyperexcitability and anxiety-linked behaviors.

IF 9 1区医学

EMBO Molecular Medicine Pub Date : 2025-02-01 Epub Date: 2025-02-05 DOI: 10.1038/s44321-024-00179-y

Weonjin Yu, Yixin Xiao, Anusha Jayaraman, Yi-Chun Yen, Hae Ung Lee, Sven Pettersson, H Shawn Je

{"title":"Microbial metabolites tune amygdala neuronal hyperexcitability and anxiety-linked behaviors.","authors":"Weonjin Yu, Yixin Xiao, Anusha Jayaraman, Yi-Chun Yen, Hae Ung Lee, Sven Pettersson, H Shawn Je","doi":"10.1038/s44321-024-00179-y","DOIUrl":"10.1038/s44321-024-00179-y","url":null,"abstract":"Changes in gut microbiota composition have been linked to anxiety behavior in rodents. However, the underlying neural circuitry linking microbiota and their metabolites to anxiety behavior remains unknown. Using male C57BL/6J germ-free (GF) mice, not exposed to live microbes, increased anxiety-related behavior was observed correlating with a significant increase in the immediate early c-Fos gene in the basolateral amygdala (BLA). This phenomenon coincided with increased intrinsic excitability and spontaneous synaptic activity of BLA pyramidal neurons associated with reduced small conductance calcium-activated potassium (SK) channel currents. Importantly, colonizing GF mice to live microbes or the microbial-derived metabolite indoles reverted SK channel activities in BLA pyramidal neurons and reduced the anxiety behavioral phenotype. These results are consistent with a molecular mechanism by which microbes and or microbial-derived indoles, regulate functional changes in the BLA neurons. Moreover, this microbe metabolite regulation of anxiety links these results to ancient evolutionarily conserved defense mechanisms associated with anxiety-related behaviors in mammals.","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":" ","pages":"249-264"},"PeriodicalIF":9.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11821874/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143255148","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Macrophage-induced enteric neurodegeneration leads to motility impairment during gut inflammation.

IF 9 1区医学

EMBO Molecular Medicine Pub Date : 2025-02-01 Epub Date: 2025-01-06 DOI: 10.1038/s44321-024-00189-w

Mona Breßer, Kevin D Siemens, Linda Schneider, Jonah E Lunnebach, Patrick Leven, Tim R Glowka, Kristin Oberländer, Elena De Domenico, Joachim L Schultze, Joachim Schmidt, Jörg C Kalff, Anja Schneider, Sven Wehner, Reiner Schneider

{"title":"Macrophage-induced enteric neurodegeneration leads to motility impairment during gut inflammation.","authors":"Mona Breßer, Kevin D Siemens, Linda Schneider, Jonah E Lunnebach, Patrick Leven, Tim R Glowka, Kristin Oberländer, Elena De Domenico, Joachim L Schultze, Joachim Schmidt, Jörg C Kalff, Anja Schneider, Sven Wehner, Reiner Schneider","doi":"10.1038/s44321-024-00189-w","DOIUrl":"10.1038/s44321-024-00189-w","url":null,"abstract":"Current studies pictured the enteric nervous system and macrophages as modulators of neuroimmune processes in the inflamed gut. Expanding this view, we investigated the impact of enteric neuron-macrophage interactions on postoperative trauma and subsequent motility disturbances, i.e., postoperative ileus. In the early postsurgical phase, we detected strong neuronal activation, followed by transcriptional and translational signatures indicating neuronal death and synaptic damage. Simultaneously, our study revealed neurodegenerative profiles in macrophage-specific transcriptomes after postoperative trauma. Validating the role of resident and monocyte-derived macrophages, we depleted macrophages by CSF-1R-antibodies and used CCR2-/- mice, known for reduced monocyte infiltration, in POI studies. Only CSF-1R-antibody-treated animals showed decreased neuronal death and lessened synaptic decay, emphasizing the significance of resident macrophages. In human gut samples taken early and late during abdominal surgery, we substantiated the mouse model data and found reactive and apoptotic neurons and dysregulation in synaptic genes, indicating a species' overarching mechanism. Our study demonstrates that surgical trauma activates enteric neurons and induces neurodegeneration, mediated by resident macrophages, introducing neuroprotection as an option for faster recovery after surgery.","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":"17 2","pages":"301-335"},"PeriodicalIF":9.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11822118/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143406508","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Exposomics: a review of methodologies, applications, and future directions in molecular medicine. Exposomics: A review of methodologies, applications, and future directions in molecular medicine.

IF 9 1区医学

EMBO Molecular Medicine Pub Date : 2025-01-27 DOI: 10.1038/s44321-025-00191-w

Melissa Wan, Elisabeth M Simonin, Mary Margaret Johnson, Xinyue Zhang, Xiangping Lin, Peng Gao, Chirag J Patel, Aroub Yousuf, Michael P Snyder, Xiumei Hong, Xiaobin Wang, Vanitha Sampath, Kari C Nadeau

{"title":"Exposomics: a review of methodologies, applications, and future directions in molecular medicine.","authors":"Melissa Wan, Elisabeth M Simonin, Mary Margaret Johnson, Xinyue Zhang, Xiangping Lin, Peng Gao, Chirag J Patel, Aroub Yousuf, Michael P Snyder, Xiumei Hong, Xiaobin Wang, Vanitha Sampath, Kari C Nadeau","doi":"10.1038/s44321-025-00191-w","DOIUrl":"https://doi.org/10.1038/s44321-025-00191-w","url":null,"abstract":"The exposome is the measure of all the exposures of an individual in a lifetime and how those exposures relate to health. Exposomics is the emerging field of research to measure and study the totality of the exposome. Exposomics can assist with molecular medicine by furthering our understanding of how the exposome influences cellular and molecular processes such as gene expression, epigenetic modifications, metabolic pathways, and immune responses. These molecular alterations can aid as biomarkers for the diagnosis, disease prediction, early detection, and treatment and offering new avenues for personalized medicine. Advances in high throughput omics and other technologies as well as increased computational analytics is enabling comprehensive measurement and sophisticated analysis of the exposome to elucidate their cumulative and combined impacts on health, which can enable individuals, communities, and policymakers to create programs, policies, and protections that promote healthier environments and people. This review provides an overview of the potential role of exposomics in molecular medicine, covering its history, methodologies, current research and applications, and future directions.","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":" ","pages":""},"PeriodicalIF":9.0,"publicationDate":"2025-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143052072","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Improving the odds of survival: transgenerational effects of infections.

IF 9 1区医学

EMBO Molecular Medicine Pub Date : 2025-01-22 DOI: 10.1038/s44321-025-00192-9

Victoria M Spanou, Theano P Andriopoulou, Evangelos J Giamarellos-Bourboulis, Mihai G Netea

{"title":"Improving the odds of survival: transgenerational effects of infections.","authors":"Victoria M Spanou, Theano P Andriopoulou, Evangelos J Giamarellos-Bourboulis, Mihai G Netea","doi":"10.1038/s44321-025-00192-9","DOIUrl":"https://doi.org/10.1038/s44321-025-00192-9","url":null,"abstract":"Recent studies argue for a novel concept of the role of chromatin as a carrier of epigenetic memory through cellular and organismal generations, defining and coordinating gene activity states and physiological functions. Environmental insults, such as exposures to unhealthy diets, smoking, toxic compounds, and infections, can epigenetically reprogram germ-line cells and influence offspring phenotypes. This review focuses on intergenerational and transgenerational epigenetic inheritance in different plants, animal species and humans, presenting the up-to-date evidence and arguments for such effects in light of Darwinian and Lamarckian evolutionary theories. An overview of the epigenetic changes induced by infection or other immune challenges is presented, and how these changes, known as epimutations, contribute to shaping offspring phenotypes. The mechanisms that mediate the transmission of epigenetic alterations via the germline are also discussed. Understanding the relationship between environmental fluctuations, epigenetic changes, resistance, and susceptibility to diseases is critical for unraveling disease etiology and adaptive evolution.","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":" ","pages":""},"PeriodicalIF":9.0,"publicationDate":"2025-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143022776","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Gut microbiota interact with breast cancer therapeutics to modulate efficacy. 肠道微生物群与乳腺癌治疗药物相互作用以调节疗效。

IF 11.1 1区医学

EMBO Molecular Medicine Pub Date : 2025-01-16 DOI: 10.1038/s44321-024-00185-0

Alana A Arnone,Katherine Ansley,Arielle L Heeke,Marissa Howard-McNatt,Katherine L Cook

引用次数: 0

Bi-allelic variants in WDR47 cause a complex neurodevelopmental syndrome. WDR47的双等位基因变异导致复杂的神经发育综合征。

IF 9 1区医学

EMBO Molecular Medicine Pub Date : 2025-01-01 Epub Date: 2024-11-28 DOI: 10.1038/s44321-024-00178-z

Efil Bayam, Peggy Tilly, Stephan C Collins, José Rivera Alvarez, Meghna Kannan, Lucile Tonneau, Elena Brivio, Bruno Rinaldi, Romain Lecat, Noémie Schwaller, Ludovica Cotellessa, Sateesh Maddirevula, Fabiola Monteiro, Carlos M Guardia, João Paulo Kitajima, Fernando Kok, Mitsuhiro Kato, Ahlam A A Hamed, Mustafa A Salih, Saeed Al Tala, Mais O Hashem, Hiroko Tada, Hirotomo Saitsu, Mariano Stabile, Paolo Giacobini, Sylvie Friant, Zafer Yüksel, Mitsuko Nakashima, Fowzan S Alkuraya, Binnaz Yalcin, Juliette D Godin

{"title":"Bi-allelic variants in WDR47 cause a complex neurodevelopmental syndrome.","authors":"Efil Bayam, Peggy Tilly, Stephan C Collins, José Rivera Alvarez, Meghna Kannan, Lucile Tonneau, Elena Brivio, Bruno Rinaldi, Romain Lecat, Noémie Schwaller, Ludovica Cotellessa, Sateesh Maddirevula, Fabiola Monteiro, Carlos M Guardia, João Paulo Kitajima, Fernando Kok, Mitsuhiro Kato, Ahlam A A Hamed, Mustafa A Salih, Saeed Al Tala, Mais O Hashem, Hiroko Tada, Hirotomo Saitsu, Mariano Stabile, Paolo Giacobini, Sylvie Friant, Zafer Yüksel, Mitsuko Nakashima, Fowzan S Alkuraya, Binnaz Yalcin, Juliette D Godin","doi":"10.1038/s44321-024-00178-z","DOIUrl":"10.1038/s44321-024-00178-z","url":null,"abstract":"Brain development requires the coordinated growth of structures and cues that are essential for forming neural circuits and cognitive functions. The corpus callosum, the largest interhemispheric connection, is formed by the axons of callosal projection neurons through a series of tightly regulated cellular events, including neuronal specification, migration, axon extension and branching. Defects in any of those steps can lead to a range of disorders known as syndromic corpus callosum dysgenesis (CCD). We report five unrelated families carrying bi-allelic variants in WDR47 presenting with CCD together with other neuroanatomical phenotypes such as microcephaly and enlarged ventricles. Using in vitro and in vivo mouse models and complementation assays, we show that WDR47 is required for survival of callosal neurons by contributing to the maintenance of mitochondrial and microtubule homeostasis. We further propose that severity of the CCD phenotype is determined by the degree of the loss of function caused by the human variants. Taken together, we identify WDR47 as a causative gene of a new neurodevelopmental syndrome characterized by corpus callosum abnormalities and other neuroanatomical malformations.","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":" ","pages":"129-168"},"PeriodicalIF":9.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11730659/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142749651","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

BMP-9 mediates fibroproliferation in fibrodysplasia ossificans progressiva through TGF-β signaling. BMP-9通过TGF-β信号介导进行性骨化纤维发育不良的纤维增殖。

IF 9 1区医学

EMBO Molecular Medicine Pub Date : 2025-01-01 Epub Date: 2024-12-03 DOI: 10.1038/s44321-024-00174-3

Chengzhu Zhao, Yoshiko Inada, Souta Motoike, Daisuke Kamiya, Kyosuke Hino, Makoto Ikeya

{"title":"BMP-9 mediates fibroproliferation in fibrodysplasia ossificans progressiva through TGF-β signaling.","authors":"Chengzhu Zhao, Yoshiko Inada, Souta Motoike, Daisuke Kamiya, Kyosuke Hino, Makoto Ikeya","doi":"10.1038/s44321-024-00174-3","DOIUrl":"10.1038/s44321-024-00174-3","url":null,"abstract":"Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disorder presenting with progressive heterotopic ossification (HO) in soft tissues. Early-stage FOP is characterized by recurrent episodes of painful tissue swelling (flare-ups), with numerous proliferation-activated mesenchymal stromal cells (MSCs) subsequently causing HO. However, the mechanisms underlying flare-up progression remain unclear. In this study, we evaluated the proliferation of MSCs obtained from FOP patient-derived induced pluripotent stem cells (FOP-iPSCs) to elucidate the mechanisms underlying flare-ups and found that bone morphogenetic protein (BMP)-9 mediated enhanced proliferation by abnormal activation of transforming growth factor (TGF)-β signaling pathway in MSCs from FOP-iPSCs. In FOP model mice, elevated BMP-9 levels correlated with elevated phosphorylation of SMAD2/3 and increased cellular proliferation in the affected tissues, while systemic BMP-9 neutralization and knockout mitigated flare-ups and HO. Thus, BMP-9 aberrantly transduces TGF-β signaling and induces fibroproliferation, initiating flare-ups. This study provides novel insights into the development of future FOP therapies.","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":" ","pages":"112-128"},"PeriodicalIF":9.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11729865/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142767249","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0