Cellular and Molecular Life Sciences最新文献

{"title":"Retinoic acid drives surface epithelium fate determination through the TCF7-MSX2 axis.","authors":"Huaxing Huang, Jiafeng Liu, Fengjiao An, Siqi Wu, Huizhen Guo, Bofeng Wang, Kunlun Mo, Ying Huang, Jieying Tan, Jin Zhu, Zesong Lin, Zhuo Han, Mingsen Li, Li Wang, Zhen Mao, Hong Ouyang","doi":"10.1007/s00018-024-05525-4","DOIUrl":"10.1007/s00018-024-05525-4","url":null,"abstract":"<p><p>Understanding how embryonic progenitors decode extrinsic signals and transform into lineage-specific regulatory networks to drive cell fate specification is a fundamental, yet challenging question. Here, we develop a new model of surface epithelium (SE) differentiation induced by human embryonic stem cells (hESCs) using retinoic acid (RA), and identify BMP4 as an essential downstream signal in this process. We show that the retinoid X receptors, RXRA and RXRB, orchestrate SE commitment by shaping lineage-specific epigenetic and transcriptomic landscapes. Moreover, we find that TCF7, as a RA effector, regulates the transition from pluripotency to SE initiation by directly silencing pluripotency genes and activating SE genes. MSX2, a downstream activator of TCF7, primes the SE chromatin accessibility landscape and activates SE genes. Our work reveals the regulatory hierarchy between key morphogens RA and BMP4 in SE development, and demonstrates how the TCF7-MSX2 axis governs SE fate, providing novel insights into RA-mediated regulatory principles.</p>","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":"82 1","pages":"16"},"PeriodicalIF":6.2,"publicationDate":"2024-12-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11671468/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142892707","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Endothelial CD38-induced endothelial-to-mesenchymal transition is a pivotal driver in pulmonary fibrosis.","authors":"Min Hu, Xiao-Hui Guan, Ling-Fang Wang, Hao-Min Xu, Shu-Fen Ke, Qing-Yun Yuan, Hui-Lan Tan, Jie Wu, Guan-Hui Yu, Qi-Ming Huang, Yu Liu, Long Hu, Ke-Yu Deng, Hong-Bo Xin","doi":"10.1007/s00018-024-05548-x","DOIUrl":"10.1007/s00018-024-05548-x","url":null,"abstract":"<p><p>Idiopathic pulmonary fibrosis (IPF) is a prevalent interstitial lung disease with high mortality. CD38 is a main enzyme for intracellular nicotinamide adenine dinucleotide (NAD⁺) degradation in mammals. It has been reported that CD38 participated in pulmonary fibrosis through promoting alveolar epithelial cells senescence. However, the roles of endothelial CD38 in pulmonary fibrosis remain unknown. In the present study, we observed that the elevated expression of CD38 was related to endothelial-to-mesenchymal transition (EndMT) of lung tissues in IPF patients and bleomycin (BLM)-induced pulmonary fibrosis mice and also in human umbilical vein endothelial cells (HUVECs) treated with BLM. Micro-computed tomography (MCT) and histopathological staining showed that endothelial cell-specific CD38 knockout (CD38^EndKO) remarkably attenuated BLM-induced pulmonary fibrosis. In addition, CD38^EndKO significantly inhibited TGFβ-Smad3 pathway-mediated excessive extracellular matrix (ECM), reduced Toll-like receptor4-Myeloid differentiation factor88-Mitogen-activated protein kinases (TLR4-MyD88-MAPK) pathway-mediated endothelial inflammation and suppressed nicotinamide adenine dinucleotide phosphate oxidases1 (NOX1)-mediated oxidative stress. Furthermore, we demonstrated that 3-TYP, a SIRT3-specific inhibitor, markedly reversed the protective effect of HUVECs^CD38KD cells and 78 C, a CD38-specific inhibitor, on BLM-induced EndMT in HUVECs. Therefore, we concluded that CD38^EndKO significantly ameliorated BLM-induced pulmonary fibrosis through inhibiting ECM, endothelial inflammation and oxidative stress, further alleviating EndMT in mice. Our findings suggest that endothelial CD38 may be a new therapeutic target for the prevention and treatment of pulmonary fibrosis clinically.</p>","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":"82 1","pages":"30"},"PeriodicalIF":6.2,"publicationDate":"2024-12-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11671674/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142892577","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Platelet stimulation-regulated expression of ILK and ITGB3 contributes to intrahepatic cholangiocarcinoma progression through FAK/PI3K/AKT pathway activation.","authors":"Wei Yao, Kai Zhao, Xiangyu Li","doi":"10.1007/s00018-024-05526-3","DOIUrl":"10.1007/s00018-024-05526-3","url":null,"abstract":"<p><strong>Objective: </strong>Intrahepatic cholangiocarcinoma (iCCA) is a highly lethal hepatobiliary malignancy with an increasing incidence annually. Extensive research has elucidated the existence of a reciprocal interaction between platelets and cancer cells, which promotes tumor proliferation and metastasis. This study aims to investigate the function and mechanism underlying iCCA progression driven by the interplay between platelets and tumor cells, aiming to provide novel therapeutic strategies for iCCA.</p><p><strong>Methods: </strong>The associations between platelets and cancer development were investigated by analyzing the peripheral blood platelet count, degree of platelet activation and infiltration in the microenvironment of patients with iCCA. By co-culturing tumor cells with platelets, the influence of platelet stimulation on the epithelial-mesenchymal transition (EMT), proliferation, and metastasis of iCCA cells was assessed through in vitro and in vivo experiments. Quantitative proteomic profiling was conducted to identify key downstream targets that were altered in tumor cells following platelet stimulation. The RNA interference technique was utilized to investigate the impacts of gene silencing on the malignant biological behaviors of tumor cells.</p><p><strong>Results: </strong>Compared with healthy adults, patients with iCCA presented significantly higher levels of peripheral blood platelet counts, platelet activation and infiltration degrees, which were also found to be correlated with patient prognosis. Platelet stimulation greatly facilitated the EMT of iCCA cells, leading to enhanced proliferative and metastatic capabilities. Mechanistically, proteomic profiling identified a total of 67 up-regulated and 40 down-regulated proteins in iCCA cells co-cultured with platelets. Among these proteins, two elevated targets ILK and ITGB3, were further demonstrated to be partially responsible for platelet-induced iCCA progression, which might depend on their regulatory effects on FAK/PI3K/AKT signaling transduction.</p><p><strong>Conclusions: </strong>Our data revealed that platelet-related indices were abnormally ascendant in iCCA patients compared to healthy adults. Co-culturing with platelets enhanced the progression of EMT, and the motility and viability of iCCA cells in vitro and in vivo. Proteomic profiling discovered that platelets promoted the development of iCCA through FAK/PI3K/AKT pathway by means of elevating the expression of ILK and ITGB3, indicating that both proteins are promising therapeutic targets for iCCA with the guidance of platelet-related indices.</p>","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":"82 1","pages":"19"},"PeriodicalIF":6.2,"publicationDate":"2024-12-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11671465/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142892700","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Gram-negative bacteria-driven increase of cytosolic phospholipase A2 leads to activation of Kupffer cells.","authors":"Hao Lin, Andreas Wieser, Jiang Zhang, Ivonne Regel, Hanno Nieß, Julia Mayerle, Alexander L Gerbes, Side Liu, Christian J Steib","doi":"10.1007/s00018-024-05451-5","DOIUrl":"10.1007/s00018-024-05451-5","url":null,"abstract":"<p><p>Bacterial infections are prevalent and the major cause of morbidity and mortality in cirrhosis. Activation of human Kupffer cells (HKCs) from livers is essential for human innate immunity. Cytosolic phospholipase A2 (cPLA2) plays a crucial role in the control and balance of innate immune and inflammatory reactions. Uncharacterized is the role of cPLA2 in HKC activation by bacterial infection. This work aimed to determine the function and mechanism of cPLA2 in gram-negative bacteria (GNB)-induced HKC activation. In this study, we found that Escherichia coli (E. coli)-induced activation of HKCs led to a rise in cPLA2 mRNA and protein expression, where the ERK and NF-κB pathways were concurrently triggered. Luciferase activity of cPLA2' promoters, PLA2G4A promoters, was enhanced with the stimulation of E. coli or co-transfection with STAT3 or RelB in HKCs. E. coli massively boosted the binding activity of STAT3 and RelB to the specific regions of the PLA2G4A promoter as measured by ChIP-qPCR. The E. coli-ERK-STAT3 and E. coli-non-canonical NF-κB-RelB signaling axes were then identified using pathway inhibitors and transcription factors in the rescue experiments during E. coli-induced HKC activation. In conclusion, we discovered that cPLA2 is necessary for E. coli-induced HKC activation, and the underlying mechanism could be the transcriptional regulation of STAT3 and RelB on the PLA2G4A promoter following the ERK and non-canonical NF-κB signaling activation, implying that the regulation of cPLA2 expression via the E. coli-ERK/non-canonical NF-κB-STAT3/RelB signaling axis could be effective for controlling GNB-induced HKC activation in cirrhotic patients.</p>","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":"82 1","pages":"22"},"PeriodicalIF":6.2,"publicationDate":"2024-12-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11671446/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142892581","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction: Animal regeneration in the era of transcriptomics.","authors":"Loïc Bideau, Pierre Kerner, Jerome Hui, Michel Vervoort, Eve Gazave","doi":"10.1007/s00018-024-05488-6","DOIUrl":"10.1007/s00018-024-05488-6","url":null,"abstract":"","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":"82 1","pages":"25"},"PeriodicalIF":6.2,"publicationDate":"2024-12-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11671442/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142892574","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"E3 ubiquitin ligase TRIM2 identified as a novel suppressor of CYP11B2 and aldosterone production.","authors":"Liang Chen, Xuan Hu, Gang Wang, Fang Yu, Zhe Dai, Xiaobin Jian, Yong Li, Wan Xiang, Zhe Meng","doi":"10.1007/s00018-024-05545-0","DOIUrl":"10.1007/s00018-024-05545-0","url":null,"abstract":"<p><p>Aldosterone-producing adenoma (APA) is a leading cause of primary aldosteronism (PA), a condition marked by excessive aldosterone secretion. CYP11B2, the aldosterone synthase, plays a critical role in aldosterone biosynthesis and the development of APA. Despite its significance, encoding regulatory mechanisms governing CYP11B2, particularly its degradation, remain poorly understood. In this study, we sought to uncover novel regulators of CYP11B2 stability by conducting a siRNA screen targeting E3 ubiquitin ligases. Our results identified TRIM2 as a key negative regulator of CYP11B2, where its overexpression led to a significant reduction in CYP11B2 protein levels and a concomitant decrease in aldosterone production in adrenal tumor cells. Mechanistically, we demonstrated that TRIM2 interacts with CYP11B2 via its RBCC domain, promoting K29/48-linked polyubiquitination and destabilization of CYP11B2. Further results revealed that TRIM2 is downregulated in APA tissues, showing differential expression between the zona glomerulosa (ZG) and zona fasciculata (ZF) of normal adrenal tissue. These findings highlight TRIM2 as a novel modulator of aldosterone synthesis through CYP11B2 degradation, offering a potential therapeutic target for APA.</p>","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":"82 1","pages":"27"},"PeriodicalIF":6.2,"publicationDate":"2024-12-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11671668/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142892576","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction: Human myofibroblasts increase the arrhythmogenic potential of human induced pluripotent stem cell-derived cardiomyocytes.","authors":"Robert D Johnson, Ming Lei, John H McVey, Patrizia Camelliti","doi":"10.1007/s00018-024-05492-w","DOIUrl":"10.1007/s00018-024-05492-w","url":null,"abstract":"","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":"82 1","pages":"20"},"PeriodicalIF":6.2,"publicationDate":"2024-12-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11671666/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142892575","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Adaptive remodeling of rat adrenomedullary stimulus-secretion coupling in a chronic hypertensive environment.","authors":"Vincent Paillé, Joohee Park, Bertrand Toutain, Jennifer Bourreau, Pierre Fontanaud, Frédéric De Nardi, Claudie Gabillard-Lefort, Dimitri Bréard, David Guilet, Daniel Henrion, Christian Legros, Nathalie C Guérineau","doi":"10.1007/s00018-024-05524-5","DOIUrl":"10.1007/s00018-024-05524-5","url":null,"abstract":"<p><p>Chronic elevated blood pressure impinges on the functioning of multiple organs and therefore harms body homeostasis. Elucidating the protective mechanisms whereby the organism copes with sustained or repetitive blood pressure rises is therefore a topical challenge. Here we address this issue in the adrenal medulla, the master neuroendocrine tissue involved in the secretion of catecholamines, influential hormones in blood pressure regulation. Combining electrophysiological techniques with catecholamine secretion assays on acute adrenal slices from spontaneously hypertensive rats, we show that chromaffin cell stimulus-secretion coupling is remodeled, resulting in a less efficient secretory function primarily upon sustained cholinergic challenges. The remodeling is supported by revamped both cellular and tissular mechanisms. This first includes a decrease in chromaffin cell excitability in response to sustained electrical stimulation. This hallmark was observed both experimentally and in a computational chromaffin cell model, and occurs with concomitant changes in voltage-gated ion channel expression. The cholinergic transmission at the splanchnic nerve-chromaffin cell synapses and the gap junctional communication between chromaffin cells are also weakened. As such, by disabling its competence to release catecholamines in response sustained stimulations, the hypertensive medulla has elaborated an adaptive shielding mechanism against damaging effects of redundant elevated catecholamine secretion and associated blood pressure.</p>","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":"82 1","pages":"31"},"PeriodicalIF":6.2,"publicationDate":"2024-12-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11671677/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142892570","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exogenous acetate attenuates inflammatory responses through HIF-1α-dependent glycolysis regulation in macrophage.","authors":"Na Li, Yi Gong, Yalin Zhu, Bo Li, Changli Wang, Zhefan Wang, Jun Wang, Jie Huang, Jinjun Bian, Yan Zhang","doi":"10.1007/s00018-024-05521-8","DOIUrl":"10.1007/s00018-024-05521-8","url":null,"abstract":"<p><p>Cytokine storm is a hallmark for acute systemic inflammatory disease like sepsis. Intrinsic microbiome-derived short-chain fatty acid (SCFAs) like acetate modulates immune cell function and metabolism has been well studied. However, it remains poorly investigated about the effects and the underlying mechanism of exogenous acetate in acute inflammation like sepsis. Here, we observed that serum acetate accumulates in patients undergoing abdominal gastrointestinal surgery and in septic mice. Short exposure to high-dose exogenous acetate protects mice from sepsis by inhibiting glycolysis in macrophages, both in vivo and in vitro. Hypoxia-inducible factor 1 subunit alpha (HIF-1α) stabilization or overexpression reverses the decreased glycolysis and pro-inflammatory cytokine production in macrophages and abrogates acetate's protective effect in septic mice. Meanwhile, we also found acetyl-CoA synthetase-2, but not GPR41 or GPR43, plays a key role in acetate's immunosuppressive effect. Acetate transiently increases acetyl-coenzyme A production, promoting histone acetylation and decreasing acetyl-transfer to NF-κB p65. These findings suggest that short exposure to mM-level acetate inhibits macrophage immune response linked to HIF-1α-dependent glycolysis. Taken together, we demonstrate short-term exposure of exogenous acetate could regulate inflammatory responses through attenuating HIF-1α-dependent glycolysis.</p>","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":"82 1","pages":"21"},"PeriodicalIF":6.2,"publicationDate":"2024-12-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11671453/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142892579","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting STMN2 for neuroprotection and neuromuscular recovery in Spinal Muscular Atrophy: evidence from in vitro and in vivo SMA models.","authors":"Elisa Pagliari, Michela Taiana, Paolo Manzini, Luca Sali, Lorenzo Quetti, Letizia Bertolasi, Samanta Oldoni, Valentina Melzi, Giacomo Comi, Stefania Corti, Monica Nizzardo, Federica Rizzo","doi":"10.1007/s00018-024-05550-3","DOIUrl":"10.1007/s00018-024-05550-3","url":null,"abstract":"<p><p>The development of ground-breaking Survival Motor Neuron (SMN) replacement strategies has revolutionized the field of Spinal Muscular Atrophy (SMA) research. However, the limitations of these therapies have now become evident, highlighting the need for the development of complementary targets beyond SMN replacement. To address these challenges, here we explored, in in vitro and in vivo disease models, Stathmin-2 (STMN2), a neuronal microtubule regulator implicated in neurodegenerative diseases like Amyotrophic Lateral Sclerosis (ALS), as a novel SMN-independent target for SMA therapy. Our findings revealed that STMN2 overexpression effectively restored axonal growth and outgrowth defects in induced pluripotent stem cell-(iPSC)-derived motor neurons (MNs) from SMA patients. Intracerebroventricular administration of adeno-associated virus serotype 9 (AAV9) carrying Stmn2 cDNA significantly ameliorated survival rates, motor functions, muscular and neuromuscular junction pathological features in SMA mice, mirrored by in vitro outcomes. Overall, this pioneering study not only provides insight into the therapeutic potential of STMN2 in SMA, but also suggests its broader applications for MN diseases, marking a substantial step forward in addressing the multifaceted challenges of neurological diseases treatment.</p>","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":"82 1","pages":"29"},"PeriodicalIF":6.2,"publicationDate":"2024-12-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11671459/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142892715","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}