JCI insight最新文献_第4页

Posttranscriptional control of hepatic CEACAM1 3'UTR by human antigen R (HuR) mitigates sterile liver inflammation. 人抗原R （HuR）转录后控制肝脏CEACAM1 3'UTR减轻无菌性肝脏炎症。

IF 6.1 1区医学

JCI insight Pub Date : 2025-09-23 DOI: 10.1172/jci.insight.194227

Brian Cheng, Tristan D Tibbe, Siyuan Yao, Megan Wei, Zeriel Y Wong, Taylor Torgerson, Richard Chiu, Aanchal S Kasargod, Kojiro Nakamura, Monica Cappelletti, Myung Sim, Douglas G Farmer, Fady Kaldas, Jerzy W Kupiec-Weglinski, Kenneth J Dery

{"title":"Posttranscriptional control of hepatic CEACAM1 3'UTR by human antigen R (HuR) mitigates sterile liver inflammation.","authors":"Brian Cheng, Tristan D Tibbe, Siyuan Yao, Megan Wei, Zeriel Y Wong, Taylor Torgerson, Richard Chiu, Aanchal S Kasargod, Kojiro Nakamura, Monica Cappelletti, Myung Sim, Douglas G Farmer, Fady Kaldas, Jerzy W Kupiec-Weglinski, Kenneth J Dery","doi":"10.1172/jci.insight.194227","DOIUrl":"10.1172/jci.insight.194227","url":null,"abstract":"Hepatic ischemia-reperfusion injury (IRI) disrupts cellular signaling pathways and contributes to early allograft dysfunction (EAD) in orthotopic liver transplantation (OLT). In this study, we found that the hepatic RNA binding protein Human Antigen R (HuR) regulated the 3' untranslated region (UTR) of Carcinoembryonic Antigen-Related Cell Adhesion Molecule 1 (Ceacam1) following ischemic stress. Hepatocyte-specific preinjury HuR-null mice exhibited elevated LDH-5 isoenzyme activity and reduced Ceacam1-S expression, reflecting tissue-specific injury. In situ hybridization demonstrated that the stability of Ceacam1 mRNA depended on HuR. Luciferase assays identified Ceacam1 3'UTR cis-elements responsive to high oxygen tension. HuR-targeting short-activating RNAs (saRNAs) preferentially induced the alternative splicing of Ceacam1-S. Antisense oligos directed to the Ceacam1 3'UTR protected WT mice against acute liver injury. In the clinical arm, increased HuR and CEACAM1 expression were associated with reduced proinflammatory phenotype and a lower incidence of EAD in patients with OLT (n = 164). Human discarded livers with elevated ELAVL1/CEACAM1 levels correlated with improved tissue homeostasis. These findings suggest that HuR regulation of Ceacam1 represents a key determinant of donor tissue quality and offers a potential target for future therapeutic strategies in OLT recipients.","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":"10 18","pages":""},"PeriodicalIF":6.1,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12487867/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145124758","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

Nf2/FGFR1/AKT axis directs cranial neural crest-derived skull morphogenesis via collagen synthesis and trafficking. Nf2/FGFR1/AKT轴通过胶原合成和运输指导颅神经嵴衍生的颅骨形态发生。

IF 6.1 1区医学

JCI insight Pub Date : 2025-09-23 DOI: 10.1172/jci.insight.191112

Yuping Huang, Junguang Liao, Panpan Shen, Yiliang He, Fuju Sun, Qi Zhang, Changlin Zheng, Xingen Zhang, Haibo Li, Guiqian Chen

{"title":"Nf2/FGFR1/AKT axis directs cranial neural crest-derived skull morphogenesis via collagen synthesis and trafficking.","authors":"Yuping Huang, Junguang Liao, Panpan Shen, Yiliang He, Fuju Sun, Qi Zhang, Changlin Zheng, Xingen Zhang, Haibo Li, Guiqian Chen","doi":"10.1172/jci.insight.191112","DOIUrl":"10.1172/jci.insight.191112","url":null,"abstract":"Cranial neural crest cells (CNCs) play a critical role in craniofacial bone morphogenesis, engaging in intricate interactions with various molecular signals to ensure proper development, yet the molecular scaffolds coordinating these processes remain incompletely defined. Here, we identify neurofibromin 2 (Nf2) as a critical regulator to direct CNC-derived skull morphogenesis. Genetic ablation of Nf2 in murine CNCs causes severe craniofacial anomalies, featuring declined proliferation and increased apoptosis in osteoprogenitors, impaired type I collagen biosynthesis and trafficking, and aberrant osteogenic mineralization. Mechanistically, we uncover that Nf2 serves as a molecular linker that individually interacts with FGF receptor 1 (FGFR1) and Akt through spatially segregated phosphor-sites, and structural modeling and mutagenesis identified Ser10 and Thr230 as essential residues, with Thr230 mutation selectively ablating Akt binding while preserving FGFR1 association. Strikingly, Akt inhibition phenocopied Nf2 deficiency, reducing collagen production and Nf2 phosphorylation, whereas phospho-mimetic Nf2 (T230D) rescued CNC-derived osteogenic defects in Nf2-mutant animals. Our findings underscore the physiological significance of Nf2 as a phosphorylation-operated scaffold licensing the FGFR1/AKT axis to regulate collagen type I biogenesis and trafficking, ensuring normal CNC-derived osteogenesis and craniofacial bone development, thus exposing the Nf2/FGFR1/AKT signaling axis as a therapeutic target and promising advancements in treatment of craniofacial anomalies.","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":"10 18","pages":""},"PeriodicalIF":6.1,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12487865/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145124691","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

Mitochondrial β-oxidation of adipose-derived fatty acids by osteoblasts fuels parathyroid hormone-induced bone formation. 成骨细胞对脂肪来源的脂肪酸进行线粒体β氧化，为甲状旁腺激素诱导的骨形成提供燃料。

IF 6.1 1区医学

JCI insight Pub Date : 2025-09-23 DOI: 10.1172/jci.insight.198337

Nathalie S Alekos, Priyanka Kushwaha, Soohyun P Kim, Zhu Li, Abdullah Abood, Naomi Dirckx, Susan Aja, Joe Kodama, Jean G Garcia-Diaz, Satoru Otsuru, Elizabeth Rendina-Ruedy, Michael J Wolfgang, Ryan C Riddle

引用次数: 0

Tumor heterogeneity underlies clinical outcome and MEK inhibitor response in somatic NF1-mutant glioblastoma. 在体细胞nf1突变型胶质母细胞瘤中，肿瘤异质性是临床结果和MEK抑制剂反应的基础。

IF 6.1 1区医学

JCI insight Pub Date : 2025-09-23 DOI: 10.1172/jci.insight.192658

Sixuan Pan, Kanish Mirchia, Emily Payne, S John Liu, Nadeem Al-Adli, Zain Peeran, Poojan Shukla, Jacob S Young, Rohit Gupta, Jasper Wu, Joanna Pak, Tomoko Ozawa, Brian Na, Alyssa T Reddy, Steve E Braunstein, Joanna J Phillips, Susan Chang, David A Solomon, Arie Perry, David R Raleigh, Mitchel S Berger, Adam R Abate, Harish N Vasudevan

{"title":"Tumor heterogeneity underlies clinical outcome and MEK inhibitor response in somatic NF1-mutant glioblastoma.","authors":"Sixuan Pan, Kanish Mirchia, Emily Payne, S John Liu, Nadeem Al-Adli, Zain Peeran, Poojan Shukla, Jacob S Young, Rohit Gupta, Jasper Wu, Joanna Pak, Tomoko Ozawa, Brian Na, Alyssa T Reddy, Steve E Braunstein, Joanna J Phillips, Susan Chang, David A Solomon, Arie Perry, David R Raleigh, Mitchel S Berger, Adam R Abate, Harish N Vasudevan","doi":"10.1172/jci.insight.192658","DOIUrl":"10.1172/jci.insight.192658","url":null,"abstract":"Tumor suppressor NF1 is recurrently mutated in glioblastoma, leading to aberrant activation of Ras/rapidly accelerated fibrosarcoma (RAF)/MEK signaling. However, how tumor heterogeneity shapes the molecular landscape and efficacy of targeted therapies remains unclear. Here, we combined bulk and single-cell genomics of human somatic NF1-mutant, isocitrate dehydrogenase (IDH) wild-type glioblastomas with functional studies in cell lines and mouse intracranial tumor models to identify mechanisms of tumor heterogeneity underlying clinical outcome and MEK inhibitor response. Targeted DNA sequencing identified CDKN2A/B homozygous deletion as a poor prognostic marker in somatic NF1-mutant, but not NF1 wild-type, glioblastoma. Single-nucleus RNA sequencing of human patient NF1-mutant glioblastomas demonstrated that mesenchymal-like (MES-like) tumor cells were enriched for MEK activation signatures. Single-cell RNA-sequencing of mouse intracranial glioblastomas treated with the MEK inhibitor selumetinib identified distinct responses among tumor subpopulations. MEK inhibition selectively depleted MES-like cells, and selumetinib-resistant MES-like cells upregulated Ras signaling while resistant non-MES cells expressed markers of glial differentiation. Finally, genome-wide CRISPR interference screens validated Ras/RAF/MEK signaling as a key mediator of selumetinib response. Repression of the RAF regulator SHOC2 sensitized glioblastomas to selumetinib in vitro and in vivo, suggesting a synergistic treatment strategy. Taken together, these results highlighted the heterogeneity of NF1-mutant glioblastomas and informed future combination therapies.","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":"10 18","pages":""},"PeriodicalIF":6.1,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12487855/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145124820","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

FXR shapes an immunosuppressive microenvironment in PD-L1lo/- non-small cell lung cancer by upregulating HVEM. FXR通过上调HVEM在PD-L1lo/-非小细胞肺癌中形成免疫抑制微环境。

IF 6.1 1区医学

JCI insight Pub Date : 2025-09-23 DOI: 10.1172/jci.insight.190716

Xiaolong Xu, Bin Shang, Hancheng Wu, Xiuye Jin, Junren Wang, Jing Li, Daowei Li, Bin Liang, Xingguang Wang, Lili Su, Wenjie You, Shujuan Jiang

{"title":"FXR shapes an immunosuppressive microenvironment in PD-L1lo/- non-small cell lung cancer by upregulating HVEM.","authors":"Xiaolong Xu, Bin Shang, Hancheng Wu, Xiuye Jin, Junren Wang, Jing Li, Daowei Li, Bin Liang, Xingguang Wang, Lili Su, Wenjie You, Shujuan Jiang","doi":"10.1172/jci.insight.190716","DOIUrl":"10.1172/jci.insight.190716","url":null,"abstract":"Immune checkpoint therapy has changed cancer treatment, including non-small cell lung cancer (NSCLC). The unresponsiveness of PD-L1lo/- tumors to anti-PD-1/PD-L1 immunotherapy is attributed to alternative immune evasion mechanisms that remain elusive. We previously reported that farnesoid X receptor (FXR) was increased in PD-L1lo/- NSCLC. Herein, we found that immune checkpoint HVEM was positively correlated with FXR but inversely correlated with PD-L1 in NSCLC. HVEM was highly expressed in FXRhiPD-L1lo NSCLC. Consistently, clinically relevant FXR antagonist dose-dependently inhibited HVEM expression in NSCLC. FXR inhibited cytokine production and cytotoxicity of cocultured CD8+ T cells in vitro, and it shaped an immunosuppressive tumor microenvironment (TME) in mouse tumors in vivo through the HVEM/BTLA pathway. Clinical investigations show that the FXR/HVEM axis was associated with immunoevasive TME and inferior survival outcomes in patients with NSCLC. Mechanistically, FXR upregulated HVEM via transcriptional activation, intracellular Akt, Erk1/2 and STAT3 signals, and G1/S cycle progression in NSCLC cells. In vivo treatment experiments demonstrated that anti-BTLA immunotherapy reinvigorated antitumor immunity in TME, resulting in enhanced tumor inhibition and survival improvement in FXRhiPD-L1lo mouse Lewis lung carcinomas. In summary, our findings establish the FXR/HVEM axis as an immune evasion mechanism in PD-L1lo/- NSCLC, providing translational implications for future immunotherapy in this subgroup of patients.","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":"10 18","pages":""},"PeriodicalIF":6.1,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12487857/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145124737","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

Matrix metalloproteinases are hallmark early biomarkers and therapeutic targets in FSHD. 基质金属蛋白酶是FSHD的早期标志物和治疗靶点。

IF 6.1 1区医学

JCI insight Pub Date : 2025-09-18 DOI: 10.1172/jci.insight.195104

Usuk Jung, Erdong Wei, Haseeb Ahsan, Ana Mitanoska, Kenric Chen, Michael Kyba, Darko Bosnakovski

引用次数: 0

In-utero rescue of neurological dysfunction in a mouse model of Wiedemann-Steiner syndrome. Wiedemann-Steiner综合征小鼠模型的子宫内神经功能障碍抢救。

IF 6.1 1区医学

JCI insight Pub Date : 2025-09-16 DOI: 10.1172/jci.insight.187039

Tinna Reynisdottir, Kimberley J Anderson, Katrin Möller, Stefán Pétursson, Andrew Brinn, Katheryn P Franklin, Juan Ouyang, Asbjorg O Snorradottir, Cathleen M Lutz, Aamir R Zuberi, Valerie B DeLeon, Hans T Bjornsson

{"title":"In-utero rescue of neurological dysfunction in a mouse model of Wiedemann-Steiner syndrome.","authors":"Tinna Reynisdottir, Kimberley J Anderson, Katrin Möller, Stefán Pétursson, Andrew Brinn, Katheryn P Franklin, Juan Ouyang, Asbjorg O Snorradottir, Cathleen M Lutz, Aamir R Zuberi, Valerie B DeLeon, Hans T Bjornsson","doi":"10.1172/jci.insight.187039","DOIUrl":"10.1172/jci.insight.187039","url":null,"abstract":"Wiedemann-Steiner syndrome (WDSTS) is a rare genetic cause of intellectual disability that is primarily caused by heterozygous loss of function variants in the gene encoding the histone lysine methyltransferase 2A (KMT2A). Prior studies have shown successful postnatal amelioration of disease phenotypes for Rett, Rubinstein-Taybi and Kabuki syndromes, which are related Mendelian disorders of the epigenetic machinery. To explore whether the neurological phenotype in WDSTS is treatable in-utero, we created a mouse model carrying a loss of function variant placed between two loxP sites. Kmt2a+/LSL mice demonstrated core features of WDSTS including growth retardation, craniofacial abnormalities, and hypertrichosis as well as hippocampal memory defects. The neurological phenotypes were rescued upon restoration of KMT2A in-utero following breeding to a nestin-Cre. Together, our data provided a mouse model to explore the potential therapeutic window in WDSTS. Our work suggested that WDSTS has a window of opportunity extending at least until the mid-point of in-utero development, making WDSTS an ideal candidate for future therapeutic strategies.","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.1,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145075347","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

Abrogation of FGFR signaling blocks β-Catenin-induced adrenocortical hyperplasia and aldosterone production. 取消FGFR信号传导可阻断β-连环蛋白诱导的肾上腺皮质增生和醛固酮的产生。

IF 6.1 1区医学

JCI insight Pub Date : 2025-09-16 DOI: 10.1172/jci.insight.184863

Vasileios Chortis, Dulanjalee Kariyawasam, Mesut Berber, Nick A Guagliardo, Sining Leng, Betul Haykir, Claudio Ribeiro, Manasvi S Shah, Emanuele Pignatti, Brenna Jorgensen, Lindsey Gaston, Paula Q Barrett, Diana L Carlone, Kleiton Silva Borges, David T Breault

{"title":"Abrogation of FGFR signaling blocks β-Catenin-induced adrenocortical hyperplasia and aldosterone production.","authors":"Vasileios Chortis, Dulanjalee Kariyawasam, Mesut Berber, Nick A Guagliardo, Sining Leng, Betul Haykir, Claudio Ribeiro, Manasvi S Shah, Emanuele Pignatti, Brenna Jorgensen, Lindsey Gaston, Paula Q Barrett, Diana L Carlone, Kleiton Silva Borges, David T Breault","doi":"10.1172/jci.insight.184863","DOIUrl":"10.1172/jci.insight.184863","url":null,"abstract":"Fibroblast Growth Factor Receptors (FGFRs) are tyrosine kinase receptors critical for organogenesis and tissue maintenance, including in the adrenal gland. Here we delineate the role of FGFR2 in the morphogenesis, maintenance and function of the adrenal cortex with a focus on the zona Glomerulosa (zG). zG-specific Fgfr2 deletion (Fgfr2-cKO) resulted in impaired zG cell identity, proliferation and transdifferentiation into zona Fasciculata (zF) cells during postnatal development. In adult mice, induced deletion of Fgfr2 led to loss of mature zG cell identity, highlighting the importance of FGFR2 for the maintenance of a differentiated zG state. Strikingly, Fgfr2-cKO was sufficient to fully abrogate β-Catenin-induced zG hyperplasia and to reduce aldosterone levels. Finally, short-term treatment with pan-FGFR small molecule inhibitors suppressed aldosterone production in both wild-type and β-Catenin gain-of-function mice. These results demonstrate a critical role for FGFR signaling in adrenal morphogenesis, maintenance and function and suggest that targeting FGFR signaling may benefit patients with aldosterone excess and/or adrenal hyperplasia.","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.1,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145075308","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

Recurrent neonatal seizures increase tonic inhibition and respond to enhancers of δ-containing GABAA receptors. 新生儿复发性癫痫发作增加强直性抑制，并对含δ- GABAA受体的增强剂有反应。

IF 6.1 1区医学

JCI insight Pub Date : 2025-09-16 DOI: 10.1172/jci.insight.196152

Gage T Liddiard, Gordon F Buchanan, Mark L Schultz, Joseph Glykys

{"title":"Recurrent neonatal seizures increase tonic inhibition and respond to enhancers of δ-containing GABAA receptors.","authors":"Gage T Liddiard, Gordon F Buchanan, Mark L Schultz, Joseph Glykys","doi":"10.1172/jci.insight.196152","DOIUrl":"https://doi.org/10.1172/jci.insight.196152","url":null,"abstract":"About one-third of neonatal seizures do not respond to the first-line anticonvulsant phenobarbital, which activates phasic inhibition and whose effectiveness decreases over time. Whether enhancing tonic inhibition can treat refractory seizures or status epilepticus in neonates remains uncertain. We evaluated the effect of recurrent seizure-like events (SLE) on α5- and δ-GABAAR subunit expression and tonic inhibition in neonatal C57BL/6J mice (P6-P9, both sexes) using acute brain slices. We investigated the impact of THIP (gaboxadol) on neonatal behavioral seizures, neuronal apoptosis, and neurodegeneration in vivo. We found neonatal neocortical expression of α5- and δ-GABAA receptor (GABAAR) subunits. Blocking α5-GABAARs with L-655,708 did not affect acute neonatal SLE, whereas enhancing δ-GABAARs with THDOC, a neurosteroid, reduced them. The α5- and δ-GABAAR membrane expression increased after 8 hours of neonatal SLE, and correlated with increased δ-mediated conductance, but not α5-mediated one. Enhancing tonic inhibition was more effective in reducing recurrent neonatal SLE (8 hours) compared to early treatment. Increasing tonic inhibition reduced the duration, severity, and number of kainic acid-induced in vivo neonatal behavioral seizures without increasing neurodegeneration or apoptosis. We conclude that recurrent neonatal seizures increase tonic inhibition. Therefore, enhancing tonic inhibition may be a treatment strategy for prolonged neonatal status epilepticus.","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.1,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145075353","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

Rapid cyclic stretching of cultured human visceral smooth muscle cells promotes a synthetic, proinflammatory phenotype. 快速循环拉伸培养的人内脏平滑肌细胞促进合成，促炎表型。

IF 6.1 1区医学

JCI insight Pub Date : 2025-09-16 DOI: 10.1172/jci.insight.188669

Sharon M Wolfson, Katherine Beigel, Sierra E Anderson, Brooke Deal, Molly Weiner, Se-Hwan Lee, Deanne M Taylor, Su Chin Heo, Robert O Heuckeroth, Sohaib K Hashmi

{"title":"Rapid cyclic stretching of cultured human visceral smooth muscle cells promotes a synthetic, proinflammatory phenotype.","authors":"Sharon M Wolfson, Katherine Beigel, Sierra E Anderson, Brooke Deal, Molly Weiner, Se-Hwan Lee, Deanne M Taylor, Su Chin Heo, Robert O Heuckeroth, Sohaib K Hashmi","doi":"10.1172/jci.insight.188669","DOIUrl":"https://doi.org/10.1172/jci.insight.188669","url":null,"abstract":"Bowel smooth muscle experiences mechanical stress constantly during normal function, and pathologic mechanical stressors in disease states. We tested the hypothesis that pathologic mechanical stress could alter transcription to induce smooth muscle phenotypic class switching. To test this hypothesis, primary human intestinal smooth muscle cells (HISMCs), seeded on electrospun aligned poly-ε-caprolactone nano-fibrous scaffolds, were subjected to pathologic, high frequency (1 Hz) uniaxial 3% cyclic stretch (loaded) or kept unloaded in culture for 6 hours. RNA sequencing, qRT-PCR, and quantitative immunohistochemistry defined loading-induced changes in gene expression. NicheNet predicted how differentially expressed genes might impact HISMCs and other bowel cells. These studies showed loading induced differential expression of 4537 HISMC genes. Loaded HISMCs had a less contractile phenotype, with increased expression of synthetic SMC genes, proinflammatory cytokines, and altered expression of axon guidance molecules, growth factors, and morphogens. Many differentially expressed genes encode secreted ligands that could act cell-autonomously on smooth muscle and on other cells in the bowel wall. These data show HISMCs undergo remarkably rapid phenotypic plasticity in response to mechanical stress that may convert contractile HISMCs into proliferative, fibroblast-like cells or proinflammatory cells. These mechanical stress-induced changes in HISMC gene expression may be relevant for human bowel disease.","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.1,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145075374","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