American journal of physiology. Cell physiology最新文献

{"title":"TFEB signaling promotes autophagic degradation of NLRP3 to attenuate neuroinflammation in diabetic encephalopathy.","authors":"Yijia Lin, Lizhen Cheng, Yixin Chen, Wei Li, Qihao Guo, Ya Miao","doi":"10.1152/ajpcell.00322.2024","DOIUrl":"10.1152/ajpcell.00322.2024","url":null,"abstract":"<p><p>Diabetic encephalopathy (DE), a neurological complication of diabetes mellitus, has an unclear etiology. Shreds of evidence show that the nucleotide-binding oligomerization domain-like receptor family protein 3 (NLRP3) inflammasome-induced neuroinflammation and transcription factor EB (TFEB)-mediated autophagy impairment may take part in DE development. The cross talk between these two pathways and their contribution to DE remains to be explored. A mouse model of type 2 diabetes mellitus (T2DM) exhibiting cognitive dysfunction was created, along with high-glucose (HG) cultured BV2 cells. Following, 3-methyladenine (3-MA) and rapamycin were used to modulate autophagy. To evaluate the potential therapeutic benefits of TFEB in DE, we overexpressed and knocked down TFEB in both mice and cells. Autophagy impairment and NLRP3 inflammasome activation were noticed in T2DM mice and HG-cultured BV2 cells. The inflammatory response caused by NLRP3 inflammasome activation was decreased by rapamycin-induced autophagy enhancement, while 3-MA treatment further deteriorated it. Nuclear translocation and expression of TFEB were hampered in HG-cultured BV2 cells and T2DM mice. Exogenous TFEB overexpression boosted NLRP3 degradation via autophagy, which in turn alleviated microglial activation as well as ameliorated cognitive deficits and neuronal damage. In addition, TFEB knockdown exacerbated neuroinflammation by decreasing autophagy-mediated NLRP3 degradation. Our findings have unraveled the pathogenesis of a previously underappreciated disease, implying that the activation of NLRP3 inflammasome and impairment of autophagy in microglia are significant etiological factors in the DE. The TFEB-mediated autophagy pathway can reduce neuroinflammation by enhancing NLRP3 degradation. This could potentially serve as a viable and innovative treatment approach for DE.<b>NEW & NOTEWORTHY</b> This article delves into the intricate connections between inflammation, autophagy, diabetes, and neurodegeneration, with a particular focus on a disease that is not yet fully understood-diabetic encephalopathy (DE). TFEB emerges as a pivotal regulator in balancing autophagy and inflammation in DE. Our findings highlight the crucial function of the TFEB-mediated autophagy pathway in mitigating inflammatory damage in DE, suggesting a new treatment strategy.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C1481-C1496"},"PeriodicalIF":5.0,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142492911","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A bovine model of hypoxia-induced pulmonary hypertension reveals a gradient of immune and matrisome response with a complement signature found in circulation.","authors":"Jason Williams, Franklyn N Iheagwam, Sean P Maroney, Lauren R Schmitt, R Dale Brown, Greta M Krafsur, Maria G Frid, Maxwell C McCabe, Aneta Gandjeva, Kurt J Williams, James P Luyendyk, Anthony J Saviola, Rubin M Tuder, Kurt Stenmark, Kirk C Hansen","doi":"10.1152/ajpcell.00274.2024","DOIUrl":"10.1152/ajpcell.00274.2024","url":null,"abstract":"<p><p>Pulmonary hypertension (PH) is a progressive vascular disease characterized by vascular remodeling, stiffening, and luminal obstruction, driven by dysregulated cell proliferation, inflammation, and extracellular matrix (ECM) alterations. Despite the recognized contribution of ECM dysregulation to PH pathogenesis, the precise molecular alterations in the matrisome remain poorly understood. In this study, we employed a matrisome-focused proteomics approach to map the protein composition in a young bovine calf model of acute hypoxia-induced PH. Our findings reveal distinct alterations in the matrisome along the pulmonary vascular axis, with the most prominent changes observed in the main pulmonary artery. Key alterations included a strong immune response and wound repair signature, characterized by increased levels of complement components, coagulation cascade proteins, and provisional matrix markers. In addition, we observed upregulation of ECM-modifying enzymes, growth factors, and core ECM proteins implicated in vascular stiffening, such as collagens, periostin, tenascin-C, and fibrin(ogen). Notably, these alterations correlated with increased mean pulmonary arterial pressure and vascular remodeling. In the plasma, we identified increased levels of complement components, indicating a systemic inflammatory response accompanying the vascular remodeling. Our findings shed light on the dynamic matrisome remodeling in early-stage PH, implicating a wound-healing trajectory with distinct patterns from the main pulmonary artery to the distal vasculature. This study provides novel insights into the immune cell infiltration and matrisome alterations associated with PH pathogenesis and highlights potential biomarkers and therapeutic targets within the matrisome landscape.<b>NEW & NOTEWORTHY</b> Extensive immune cell infiltration and matrisome alterations associated with hypoxia-induced pulmonary hypertension in a large mammal model. Matrisome components correlate with increased resistance to identify candidate alterations that drive biomechanical manifestations of the disease.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C1666-C1680"},"PeriodicalIF":5.0,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142567342","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Altered Sphingolipid Profile in Response to Skeletal Muscle Injury in a Mouse Model of Type 1 Diabetes Mellitus.","authors":"Jacob M Ouellette, Michael D Mallender, Dylan J Hian-Cheong, Daniel L Scurto, James E Nicholas, Stephen J Trumble, Thomas J Hawke, Matthew P Krause","doi":"10.1152/ajpcell.00158.2024","DOIUrl":"https://doi.org/10.1152/ajpcell.00158.2024","url":null,"abstract":"<p><p>A complication of type 1 diabetes mellitus (T1DM) is diabetic myopathy which includes reduced regenerative capacity of skeletal muscle. Sphingolipids are a diverse family of lipids with roles in skeletal muscle regeneration. Some studies have found changes in sphingolipid species levels in T1DM, however, the effect of T1DM on a sphingolipid panel in regenerating skeletal muscle has not been examined. Wild type (WT) and diabetic <i>Ins2^Akita+/-</i> (Akita) mice received cardiotoxin-induced muscle injury in their left quadriceps, gastrocnemius-plantaris-soleus, and tibialis anterior muscles with the contralateral muscles serving as uninjured controls. Muscles were collected at 1, 3, 5, or 7 days post-injury. In regenerating muscle from Akita mice, lipid staining with Bodipy 493/503 revealed increased intramyocellular and total lipids as well as perilipin-1-positive cell numbers as compared with WT. Liquid chromatography-mass spectrometry of quadriceps was used to identify sphingolipid levels in skeletal muscle. The C22:0 and C24:0 ceramides were significantly elevated in uninjured Akita, while ceramide C24:1 was decreased in injured Akita compared to WT. Ceramide-1-phosphate was increased in Akita compared to WT regardless of injury, while sphingosine 1-phosphate (S1P) was elevated with injury in WT but this response was muted in Akita mice. Western blotting of key enzymes involved in sphingolipid metabolism revealed S1P lyase, the enzyme which degrades S1P irreversibly, was significantly elevated in the injured muscle in Akita mice during regeneration, in accordance with lower S1P levels. This mouse model of T1DM demonstrates sphingolipidomic changes that may contribute to delayed muscle regeneration.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":""},"PeriodicalIF":5.0,"publicationDate":"2024-11-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142749759","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"¹³C Stable Isotope Tracing Reveals Distinct Fatty Acid Oxidation Pathways in Proliferative vs. Oxidative Cells.","authors":"Julia Ritterhoff, Timothy McMillen, Hanna Foundas, Roland Palkovacs, Gernot Poschet, Arianne Caudal, Yaxin Liu, Patrick Most, Matthew Walker, Rong Tian","doi":"10.1152/ajpcell.00611.2023","DOIUrl":"https://doi.org/10.1152/ajpcell.00611.2023","url":null,"abstract":"<p><p>The TCA cycle serves as a central hub to balance catabolic and anabolic needs of the cell, where carbon moieties can either contribute to oxidative metabolism or support biosynthetic reactions. This differential TCA cycle engagement for glucose-derived carbon has been extensively studied in cultured cells, but the fate of fatty acid (FA)-derived carbons is poorly understood. To fill the knowledge gap, we have developed a strategy to culture cells with long-chain FAs without altering cell viability. By tracing ¹³C-FA we show that FA oxidation (FAO) is robust in both proliferating and oxidative cells while the metabolic pathway after citrate formation is distinct. In proliferating cells, a significant portion of carbon derived from FAO exits canonical TCA cycle as citrate and converts to unlabeled malate in cytosol. Increasing FA supply or b-oxidation does not change the partition of FA-derived carbon between cytosol and mitochondria. Oxidation of glucose competes with FA derived carbon for the canonical TCA pathway thus promoting FA carbon flowing into the alternative TCA pathway. Moreover, the coupling between FAO and the canonical TCA pathway changes with the state of oxidative energy metabolism.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":""},"PeriodicalIF":5.0,"publicationDate":"2024-11-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142749751","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Inhalation Exposure to Airborne PM_2.5 Attenuates Hepatic Metabolic Pathways through S-Nitrosylation of the Primary ER Stress Sensor.","authors":"Zhao Yang, Qi Chen, Jiemei Wang, Yining Qiu, Pattaraporn Thepsuwan, Zhengping Yi, Henry H Heng, Qinghua Sun, Xuequn Chen, Li Li, Peijian He, Ren Zhang, Kezhong Zhang","doi":"10.1152/ajpcell.00385.2024","DOIUrl":"10.1152/ajpcell.00385.2024","url":null,"abstract":"<p><p>Inhalation exposure to airborne fine particulate matter (aerodynamic diameter < 2.5 µm, PM_2.5) is known to cause metabolic dysfunction-associated steatohepatitis (MASH) and the associated metabolic syndrome. Hepatic lipid accumulation and inflammation are the key characteristics of MASH. However, the mechanism by which PM_2.5 exposure induces lipid accumulation and inflammation in the liver remains to be further elucidated. In this study, we revealed that inhalation exposure to PM_2.5 induces nitrosative stress in mouse livers by suppressing hepatic S-nitrosoglutathione reductase (GSNOR) activities, which leads to S-nitrosylation modification of the primary unfolded protein response (UPR) transducer IRE1α, an endoplasmic reticulum (ER)-resident protein kinase and endoribonuclease (RNase). S-nitrosylation suppresses RNase activity of IRE1α and subsequently decreases IRE1α-mediated splicing of the mRNA encoding X-box binding protein 1 (Xbp1) and IRE1α-dependent degradation of select microRNAs (miRNAs), including miR-200 family, miR-34, miR-223, miR-155, and miR-146, in the livers of the mice exposed to PM_2.5. Elevation of IRE1α-target miRNAs, due to impaired IRE1α RNase activity by PM_2.5-triggered S-nitrosylation, leads to decreased expression of the major regulators of fatty acid oxidation, lipolysis and anti-inflammatory response, including XBP1, SIRT1, PPARα, and PPARγ, in the liver, which account at least partially for hepatic lipid accumulation and inflammation in mice exposed to airborne PM_2.5. In summary, our study revealed a novel pathway by which PM_2.5 causes cytotoxicity and promotes MASH-like phenotypes through inducing hepatic nitrosative stress and S-nitrosylation of the primary UPR transducer and subsequent elevation of select miRNAs involved in metabolism and inflammation in the liver.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":""},"PeriodicalIF":5.0,"publicationDate":"2024-11-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142738051","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Human skeletal muscle possesses an epigenetic memory of high intensity interval training.","authors":"Andrea M Pilotto, Daniel C Turner, Raffaele Mazzolari, Emanuela Crea, Lorenza Brocca, Maria Antonietta Pellegrino, Danilo Miotti, Roberto Bottinelli, Adam P Sharples, Simone Porcelli","doi":"10.1152/ajpcell.00423.2024","DOIUrl":"https://doi.org/10.1152/ajpcell.00423.2024","url":null,"abstract":"<p><strong>Introduction: </strong>Human skeletal muscle displays an epigenetic memory of resistance exercise induced by hypertrophy. It is unknown, however, whether high-intensity interval training (HIIT) also evokes an epigenetic muscle memory. This study employed repeated training intervention interspersed with a detraining period to assess epigenetic memory of HIIT.</p><p><strong>Methods: </strong>Twenty healthy subjects (25±5yrs) completed two HIIT interventions (training and retraining) lasting 2 months, separated by 3 months of detraining. Measurements at baseline, after training, detraining and retraining included maximal oxygen consumption (V̇ O_2max). Vastus lateralis biopsies were taken for genome-wide DNA methylation and targeted gene expression analyses.</p><p><strong>Results: </strong>V̇ O_2max improved during training and retraining (p<0.001) without differences between interventions (p>0.58). Thousands of differentially methylated positions (DMPs) predominantly demonstrated a hypomethylated state after training, retained even after 3-months exercise cessation and into retraining. Five genes; ADAM19, INPP5a, MTHFD1L, CAPN2, SLC16A3 possessed differentially methylated regions (DMRs) with retained hypomethylated memory profiles and increased gene expression. The retained hypomethylation during detraining was associated with an enhancement in expression of the same genes even after 3 months of detraining. SLC16A3, INPP5a, CAPN2 are involved in lactate transport and calcium signaling.</p><p><strong>Conclusions: </strong>Despite similar physiological adaptations between training and retraining, memory profiles were found at epigenetic and gene expression level, characterized by retained hypomethylation and increased gene expression after training into long-term detraining and retraining. These genes were associated with calcium signaling and lactate transport. Whilst significant memory was not observed in physiological parameters, our novel findings indicate that human skeletal muscle possesses an epigenetic memory of HIIT.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":""},"PeriodicalIF":5.0,"publicationDate":"2024-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142680592","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cultured Primary Turtle Hepatocytes: A Cellular Model for The Study of Temperature and Anoxia.","authors":"Alexander M Myrka, Ryan Frost, Domenic Distefano, Sergey V Plotnikov, Leslie T Buck","doi":"10.1152/ajpcell.00510.2023","DOIUrl":"https://doi.org/10.1152/ajpcell.00510.2023","url":null,"abstract":"<p><p>Turtle hepatocytes are a non-excitable model for metabolic depression during low-temperature and/or anoxic overwintering conditions. Cytoskeletal structure and mitochondrial distribution are continuously modified in cells, and we hypothesized that metabolic depression would inhibit such processes as cell attachment and spreading and promote withdrawal of cell protrusions and peripheral mitochondria. After developing a methodology for culturing painted turtle hepatocytes, maintenance of cell attachment after a media change, and 2D area, were used as indicators of structural rearrangement and spreading/volume. These were measured after incubating cells at varying temperatures and with or without the inclusion of cyanide (chemical proxy for anoxia). Experiments were performed using cells from 22°C- or 5°C-acclimated turtles. Live-cell imaging was used to monitor the effect of cyanide exposure on distribution of mitochondria. We also acclimated cultured cells from 22°C-acclimated turtles to 4°C <i>in vitro</i> and scored withdrawal of protrusions. Only cells isolated from 5°C-acclimated turtles and incubated at 4°C had reduced attachment to fibronectin substrate, but cyanide exposure had no effect. These cells also had a 24% smaller 2D area than those from 22°C-acclimated turtles. There was no change in mitochondrial distribution during cyanide perfusion. Finally, 4°C acclimation <i>in vitro</i> resulted in withdrawal of protrusions over 14 days. Taken together with the results from cells acclimated to low temperature <i>in vivo</i>, this suggests inhibition of structural rearrangement and protrusion stability by low temperature acclimation, but not cyanide exposure. Our cultured primary hepatocyte system will facilitate further study of the role of structural dynamics in reversible metabolic depression.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":""},"PeriodicalIF":5.0,"publicationDate":"2024-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142650561","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cohesin <i>rad21</i> mutation dysregulates erythropoiesis and granulopoiesis output within the whole kidney marrow of adult zebrafish.","authors":"Gregory Gimenez, Maggie L Kalev-Zylinska, Ian Morison, Stefan K Bohlander, Julia A Horsfield, Jisha Antony","doi":"10.1152/ajpcell.00657.2024","DOIUrl":"https://doi.org/10.1152/ajpcell.00657.2024","url":null,"abstract":"<p><p>Cohesin complex is essential for cell division and for regulating cell type-specific gene expression programs. Mutations in genes encoding the cohesin subunits are associated with hematological malignancies, pre-leukemia and clonal hematopoiesis of indeterminate potential. In this study, we examined how cohesin mutation impacts hematopoiesis using adult zebrafish that carry heterozygous germline nonsense mutation in the cohesin subunit, <i>rad21</i> (<i>rad21+/-</i>) that is orthologous to human <i>RAD21</i>. Single cell RNA sequencing analyses showed that adult zebrafish harboring <i>rad21+/-</i> mutation exhibit significant transcriptional dysregulation within the whole kidney marrow and have altered erythroid and granulocyte output. Erythroid progenitors were expanded in <i>rad21+/-</i> and erythroid differentiation was altered. The expression profile of several erythroid genes, including <i>gata1a,</i> was dysregulated in <i>rad21+/-</i> erythroid cells. Mature granulocyte population declined in <i>rad21+/-</i>, and the transcriptional program of granulocytes was impaired but granulocytic maturation was maintained. Granulocytes from <i>rad21+/-</i> showed upregulation of stress hematopoiesis factor, <i>cebpb</i>. These findings show that normal <i>rad21</i> is required to maintain steady erythropoiesis and granulopoiesis in the adult zebrafish marrow.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":""},"PeriodicalIF":5.0,"publicationDate":"2024-11-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142643240","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"p300 Maintains Primordial Follicle Activation by Repressing <i>VEGFA</i> Transcription.","authors":"Meina He, Yaoyun Liang, Xiaoran Nie, Tuo Zhang, Danqing Zhao, Jixian Zhang, Huan Lin, Zhirui Zeng, Xingyu Song, Yitong Wang, Shiling Ran, Shuyun Zhao, Tengxiang Chen, Chunlin Zhang, Zhanhui Feng","doi":"10.1152/ajpcell.00198.2024","DOIUrl":"https://doi.org/10.1152/ajpcell.00198.2024","url":null,"abstract":"<p><p>During the reproductive life, most primordial follicles remain dormant for years or decades, while some are progressively activated for development. <u>Misactivation of primordial follicles can cause ovarian diseases,</u> <u>for example,</u> <u>premature ovarian insufficiency (POI).</u> Our results show that p300 expression increased with primordial follicle activation. Using a p300 inhibitor resulted in premature activation of primordial follicles in cultured mouse ovaries. Conversely, the ratio of primordial follicle activation was markedly decreased upon culturing with the p300 agonist. Furthermore, p300 regulated primordial follicle activation by inhibiting <i>Vegfa</i> transcription in granulosa cells. Additionally, this study was extended to potential clinical applications, showing that short-term treatment with a p300 inhibitor <i>in vitro</i> significantly increased primordial follicle activation in newborn mouse ovaries after dorsal kidney membrane transplantation in female NSG mice. Our results revealed that p300 controls the activation of primordial follicles in mammalian ovaries.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":""},"PeriodicalIF":5.0,"publicationDate":"2024-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142602600","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Metalloproteinases are involved in the regulation of prenatal tooth morphogenesis.","authors":"Eva Janečková, Jesus Juarez-Balarezo, Abigail Tucker, Eva Matalová, Kateřina Holomková, Marcia Gaete","doi":"10.1152/ajpcell.00656.2024","DOIUrl":"10.1152/ajpcell.00656.2024","url":null,"abstract":"<p><p>During development, tooth germs undergo various morphological changes resulting from interactions between the oral epithelium and ectomesenchyme. These processes are influenced by the extracellular matrix, the composition of which, along with cell adhesion and signalling, is regulated by metalloproteinases. Notably, these include matrix metalloproteinases (MMPs), a disintegrin and metalloproteinases (ADAMs), and a disintegrin and metalloproteinases with thrombospondin motifs (ADAMTSs). Our analysis of previously published scRNAseq datasets highlights that these metalloproteinases show dynamic expression patterns during tooth development, with expression in a wide range of cell types, suggesting multiple roles in tooth morphogenesis. To investigate this, Marimastat, a broad-spectrum inhibitor of MMPs, ADAMs, and ADAMTSs, was applied to <i>ex-vivo</i> cultures of mouse molar tooth germs. The treated samples exhibited significant changes in tooth germ size and morphology, including an overall reduction in size and an inversion of the typical bell shape. The cervical loop failed to extend, and the central area of the inner enamel epithelium protruded. Marimastat treatment also disrupted proliferation, cell polarization and organization compared to control tooth germs. Additionally, a decrease in laminin expression was observed, leading to a disruption in continuity of the basement membrane at the epithelial-mesenchymal junction. Elevated <i>Hif-1α</i> expression correlated with a disruption to blood vessel development around the tooth germs. These results reveal the crucial role of metalloproteinases in tooth growth, shape, cervical loop elongation, and the regulation of blood vessel formation during prenatal tooth development.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":""},"PeriodicalIF":5.0,"publicationDate":"2024-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142602598","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}