Frontiers in Cell and Developmental Biology最新文献

{"title":"Nuclear envelope proteins in cancer: revisiting the significance of LEM-domain proteins.","authors":"Amie Jobe, Sameer Mirza, Ranjit Vijayan","doi":"10.3389/fcell.2026.1789623","DOIUrl":"https://doi.org/10.3389/fcell.2026.1789623","url":null,"abstract":"<p><p>Nuclear envelope dysfunction is increasingly recognized as a driver of cancer-associated alterations in chromatin organization, genome stability, and mechanotransduction. Among inner nuclear membrane components are the LEM-domain (LEM-D) proteins LAP2/TMPO, emerin (EMD), LEMD1, LEMD2, MAN1/LEMD3, ANKLE1, and ANKLE2. Accumulating evidence links dysregulation of these proteins to hallmark cancer processes, including cell-cycle control, epithelial-mesenchymal transition, genome instability, and therapeutic resistance. This review synthesizes recent mechanistic and translational findings on LEM-D proteins in cancer, highlighting isoform-specific functions, context-dependent oncogenic versus tumor-suppressive roles, and convergence on key pathways such as Wnt/β-catenin, PI3K/AKT, MAPK, and TGF-β signaling. Concrete evidence for prognostic value varies across the LEM-D proteins. While much of the current evidence derives from transcript-level and preclinical studies, emerging data suggest that LEM-D proteins contribute to nuclear stress adaptation and may represent context-dependent therapeutic vulnerabilities. We discuss their prognostic and predictive potential, critically evaluate limitations in current datasets, and present a unifying framework linking LEM-D dysfunction to genome instability, altered signalling, and therapy resistance. Thus, despite growing evidence of therapeutic potential, these proteins are better positioned as biomarkers to guide current therapies.</p>","PeriodicalId":12448,"journal":{"name":"Frontiers in Cell and Developmental Biology","volume":"14 ","pages":"1789623"},"PeriodicalIF":4.6,"publicationDate":"2026-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13144012/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147835676","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":"<i>In vivo</i> CRISPR-mediated activation of cardiogenic genes to reprogram cardiac fibroblasts.","authors":"Suchandrima Dutta, Sophie Chen, Waqas Ahmad, Wei Huang, Yigang Wang, Jialiang Liang","doi":"10.3389/fcell.2026.1812941","DOIUrl":"https://doi.org/10.3389/fcell.2026.1812941","url":null,"abstract":"<p><strong>Background: </strong>We previously demonstrated that fibroblasts can be reprogrammed through a proliferative progenitor stage to drive both cardiomyogenesis and neovascularization. However, it remains to be determined whether cardiac fibroblasts (CFs), the primary mediators of post-injury remodeling, retain the plasticity to be concurrently redirected into cardiovascular lineages within the <i>in vivo</i> environment.</p><p><strong>Methods: </strong>This study aimed to activate endogenous cardiogenic genes (<i>Gata4</i>, <i>Nkx2</i>.5, <i>Tbx5</i>, <i>Isl1</i>, and <i>Smarcd3</i>, referred to as <i>GNTIS</i>) in CFs using a CRISPR activation (CRISPRa) system. CFs isolated from fibroblast-specific transgenic dCas9 mice were used to validate cardiogenic gene activation mediated by single-guide RNAs and VP64 activators delivered <i>via</i> adeno-associated viral vectors (AAVs). The reprogramming potential of CFs into cardiovascular lineages was further evaluated in dCas9 mice subjected to myocardial infarction followed by administration of pooled AAVs.</p><p><strong>Results: </strong>Individual <i>GNTIS</i> sgRNAs effectively upregulated their respective targets in the transfected CFs. The pooled sgRNA ^<i>GNTIS</i> induced cardiac-like phenotypes in the CFs, as demonstrated by the Nkx2.5 cardiac progenitor reporter and increased cardiac differentiation markers. Subsequently, AAV-sgRNA ^<i>GNTIS</i> was assessed <i>in vivo</i> in dCas9 mice following myocardial infarction. While global cardiac function did not reach statistical significance, <i>GNTIS</i> activation improved key hemodynamic parameters, effectively preserving cardiac performance compared to controls. Immunostaining further revealed that <i>GNTIS</i>-activated CFs exhibited the potential for transdifferentiation into cardiomyocyte-like or vascular smooth muscle cell-like lineages within the infarcted heart, which was not observed in the control group.</p><p><strong>Conclusion: </strong>This CRISPRa transgenic model provides a foundational proof of concept for <i>in vivo</i> reprogramming of CFs into cardiovascular cells.</p>","PeriodicalId":12448,"journal":{"name":"Frontiers in Cell and Developmental Biology","volume":"14 ","pages":"1812941"},"PeriodicalIF":4.6,"publicationDate":"2026-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13143979/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147835896","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":"Altered brain vascularization and transcriptional changes in embryos lacking ABCA1 support a role of cholesterol in brain angiogenesis.","authors":"Brenda Becerra, Oriana Ramírez-Herrera, Javiera Barrios, Josefina Madrid, Susan Calfunao, Fujiko Saavedra, Patricia Romo-Toledo, Jesús Juárez-Balarezo, Ignacio Casanova-Maldonado, Thomas Arnold, Verónica Palma, Dolores Busso, Nicolas Santander","doi":"10.3389/fcell.2026.1783696","DOIUrl":"https://doi.org/10.3389/fcell.2026.1783696","url":null,"abstract":"<p><strong>Introduction: </strong>Lipoproteins are the main lipid carriers in extracellular fluids and mediate the exchange of hydrophobic molecules between cells and their environment in animals, including cholesterol. Lipoprotein metabolism has been implicated in the regulation of angiogenesis, suggesting that cholesterol is important for this process, but a direct role for this lipid has not been unequivocally demonstrated, particularly in the central nervous system (CNS).</p><p><strong>Methods: </strong>Here, we used genetic and pharmacological models to address this issue in different models of CNS angiogenesis.</p><p><strong>Results: </strong>We show that inactivation of ABCA1, one of the main cholesterol efflux pumps, leads to altered brain vascularization and a longer angiogenic window, while inactivation of the bidirectional cholesterol transporter SR-B1 has no effect. These functional changes are accompanied by consistent transcriptomic changes in genes involved in cholesterol synthesis and angiogenesis. In support of the role of cholesterol, experimental reduction of this lipid in cultured brain endothelial cells leads to a transcriptomic signature showing the opposite direction in those genes.</p><p><strong>Discussion: </strong>These studies support a role for ABCA1 and cholesterol in regulating a trascriptional program governing angiogenesis in the brain.</p>","PeriodicalId":12448,"journal":{"name":"Frontiers in Cell and Developmental Biology","volume":"14 ","pages":"1783696"},"PeriodicalIF":4.6,"publicationDate":"2026-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13143920/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147835932","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":"Epigenetic regulation of the β-catenin pathway in cadmium-induced colorectal cancer progression and chemoresistance.","authors":"Rajkumar Prabhakaran, Ramkumar Muthu, Karthikeyan Mahendran, Rajkumar Thamarai, Venkatesh Subramanian, Sorimuthu Revathi, Balasubramanian Velramar, Shanmugapriya Dharani, Balachandran Ruthramurthy","doi":"10.3389/fcell.2026.1808500","DOIUrl":"https://doi.org/10.3389/fcell.2026.1808500","url":null,"abstract":"<p><p>Colorectal cancer (CRC) has become a global health issue, as exposure to toxic metals (lead, chromium, cadmium, aluminum, copper, arsenic, and mercury) has all been implicated in its development and progression through interference with the mechanisms of cell proliferation and death. Recent research suggests that cadmium (Cd) and other metals disrupt normal cellular homeostasis through epigenetic changes, particularly modifying the β-catenin signaling pathway, an important key regulator of cell proliferation, differentiation, and survival. This study explores and examines the molecular mechanisms of Cd-induced changes in DNA methylation, histone acetylation, and non-coding RNA, which increase β-catenin activation and translocation into the nucleus. Such atypical epigenetic alterations promote oncogene transcriptional upregulation and survival pathways to promote tumorigenesis and non-response to chemotherapy agents. Altered epigenome regulation and dysregulation of the β-catenin pathway exacerbate Cd's oxidative stress and inflammatory capacities, which in turn lead to tumor-promoting microenvironment capabilities. The alterations uncovered with Cd exposure and epigenetic reprogramming, as well as the altered β-catenin signaling pathways, offer additional information regarding the molecular etiology of Cd-induced CRC. This review also suggests new possible treatments involving epigenetic regulators and β-catenin signaling components as exciting therapeutic approaches to address chemotherapy resistance and improve treatment outcomes for patients with colorectal cancer who have previously been exposed to heavy metals.</p>","PeriodicalId":12448,"journal":{"name":"Frontiers in Cell and Developmental Biology","volume":"14 ","pages":"1808500"},"PeriodicalIF":4.6,"publicationDate":"2026-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13144119/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147835940","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":"Cationic nanoparticles with disrupting neutrophil extracellular traps inhibit the progression of head and neck squamous cell carcinoma.","authors":"Zhaoqiang Zhang, Yujie Kang, Bingxu Lu, Guichao Zhang, Baohan Xie, Yunyi Wang","doi":"10.3389/fcell.2026.1803439","DOIUrl":"https://doi.org/10.3389/fcell.2026.1803439","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Introduction: &lt;/strong&gt;Immune checkpoint inhibitors (ICIs) have demonstrated promising therapeutic potential in head and neck squamous cell carcinoma (HNSCC). However, their clinical efficacy remains limited due to low response rates, largely attributed to the highly immunosuppressive tumor microenvironment (TME). Neutrophil extracellular traps (NETs) have recently been implicated in tumor progression and immune regulation. Therefore, this study aims to investigate the role of NETs in the TME and metastasis of HNSCC, and then to utilize cationic nanoparticles (cNP) to efficiently disrupt NETs in order to improve the immunosuppressive TME and inhibit metastasis, thereby suppressing the progression of HNSCC.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;Histological and bioinformatics analyses were performed to evaluate NET-related signatures in HNSCC tissues and their association with immune cell infiltration. &lt;i&gt;In vitro&lt;/i&gt; (scratch, cell adhesion and cytoskeletal remodeling assay) and &lt;i&gt;in vivo&lt;/i&gt; (flow cytometry, immunofluorescence staining) experiments were conducted to investigate the effects of cationic nanoparticles (cNP) on NETs disruption, tumor cell migration, therapeutic efficacy and modulation of the TME. The underlying mechanism by which NET-DNA promotes HNSCC cell migration via CCDC25 was assessed using multiple approaches. Specifically, histological and immunohistochemical staining, western blotting, transfection, qRT-PCR, and transwell assays were performed.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;Histological analysis revealed that the expression level of NETs in HNSCC tissue was significantly higher than that in adjacent normal tissue. Bioinformatics analysis revealed that high expression of myeloperoxidase (MPO) gene is closely related to immunosuppressive cell infiltration. Further analysis revealed that arm-level gain of the MPO gene was significantly correlated with a decrease in the infiltration levels of various immune cells. &lt;i&gt;In vitro&lt;/i&gt; and &lt;i&gt;in vivo&lt;/i&gt; experiments demonstrated that cNP effectively disrupted NETs, inhibited tumor cell migration, and reversed the immunosuppressive TME. Compared with anti-PD-1 monotherapy, cNP combined with anti-PD-1 therapy synergistically inhibited tumor growth, prolonged survival, and significantly increased the proportion of CD8&lt;sup&gt;+&lt;/sup&gt; T cells and CD19&lt;sup&gt;+&lt;/sup&gt; B cells, while simultaneously inhibiting the infiltration levels of Treg cells and M-MDSCs, and promoting macrophage polarization from M2 to M1 types, significantly alleviating the immunosuppressive state of TME. Immunofluorescence staining further confirmed that cNP or cNP combined with anti-PD-1 therapy effectively reduced NET-DNA deposition in tumor tissue. Regarding migration mechanisms, NET-DNA can promote HNSCC cell migration through its receptor CCDC25.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Discussion: &lt;/strong&gt;This study reveals the key role of NETs in immune escape and metastasis of HNSCC and confirms that cNP disrupting NETs can synergist","PeriodicalId":12448,"journal":{"name":"Frontiers in Cell and Developmental Biology","volume":"14 ","pages":"1803439"},"PeriodicalIF":4.6,"publicationDate":"2026-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13143943/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147835923","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":"<i>CDKN2A/2B</i> gene variants and gene-environment interactions increase the risk of gestational diabetes mellitus in Chinese women.","authors":"Yi Zhang, Runqiu Yang, Xin Wang, Hongsong Yu","doi":"10.3389/fcell.2026.1725802","DOIUrl":"https://doi.org/10.3389/fcell.2026.1725802","url":null,"abstract":"<p><strong>Introduction: </strong>This study investigates the association between the cyclin-dependent kinase inhibitor 2A/2B (<i>CDKN2A/2B</i>) gene and gestational diabetes mellitus (GDM) in Chinese women, with a focus on potential gene-environment interactions.</p><p><strong>Methods: </strong>A case-control study was conducted with 1,566 pregnant women from Beijing, Wuhan, and Zunyi, China. Blood samples were analyzed using targeted next-generation sequencing. Logistic regression was applied to examine the relationship between gene polymorphisms, environmental exposures, and GDM. Gene-environment interactions were assessed using Excel tools developed by Knol and Andersson et al.</p><p><strong>Results: </strong>Genetic analysis revealed significant associations between two of the three loci: rs23832080 (<i>P</i> = 0.002, OR = 0.801) and rs10811661 (P = 0.00055, OR = 0.746), and GDM. Haplotype analysis showed that haplotypes of these loci were correlated with GDM (AGC: P = 0.002, OR = 0.784; AAT: <i>P</i> = 0.024, OR = 1.183; GAT: <i>P</i> = 0.043, OR = 1.247). Environmental exposure analysis indicated that ozone (O₃) and PM_2.5 were associated with GDM. Interaction analysis revealed that the wild-type alleles of rs2383208 and rs10811661 interacted with O₃, increasing the risk of GDM, while the wild-type allele of rs10811661 also interacted with PM_2.5, further elevating GDM risk.</p><p><strong>Conclusion: </strong>CDKN2A/2B gene polymorphisms, haplotypes, environmental exposure to O₃ and PM_2.5, and gene-environment interactions contribute to an increased risk of GDM in Chinese women.</p><p><strong>Trial registration: </strong>Chinese Clinical Trial Registry, chictr.org.cn, ChiCTR2000029178.</p>","PeriodicalId":12448,"journal":{"name":"Frontiers in Cell and Developmental Biology","volume":"14 ","pages":"1725802"},"PeriodicalIF":4.6,"publicationDate":"2026-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13144239/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147835657","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":"Mesenchymal stem cell-derived exosomes promote scalp rejuvenation through type XVII collagen regulation via the miR-21-5p/DKK2/Wnt pathway.","authors":"Shiyue Cui, Yuanyuan Huang, Duo Zeng, Jie Li, Chun Tang","doi":"10.3389/fcell.2026.1807877","DOIUrl":"https://doi.org/10.3389/fcell.2026.1807877","url":null,"abstract":"<p><strong>Background: </strong>Hair follicle aging is driven by COL17A1 proteolysis in hair follicle stem cells (HFSCs). Mesenchymal stem cell (MSC)-derived exosomes show promise in tissue regeneration, but their effects on COL17A1 and hair follicle aging remain unexplored.</p><p><strong>Methods: </strong>Exosomes isolated from human umbilical cord MSCs (hUC-MSCs) were evaluated in H₂O₂-induced senescent human dermal papilla cells (hDPCs), <i>ex vivo</i> human hair follicle organ culture, and C57BL/6 mouse hair regeneration model. Small RNA sequencing, dual-luciferase reporter assay, and rescue experiments were performed to elucidate the mechanism.</p><p><strong>Results: </strong>Exosome treatment reduced SA-β-gal-positive cells from 67.5% to 21.4%, upregulated COL17A1 mRNA by 2.67-fold (with protein restoration to 0.89-fold of control levels), enhanced hair follicle elongation by 47.4%, and achieved 92.4% hair coverage in mice versus 45.6% for controls, outperforming minoxidil (78.3%). miR-21-5p was identified as the most abundant exosomal miRNA and confirmed to directly target DKK2, a Wnt antagonist. DKK2 suppression was associated with Wnt/β-catenin pathway activation and upregulation of COL17A1 expression. miR-21-5p inhibitor partially blocked exosome effects, validating this axis.</p><p><strong>Conclusion: </strong>hUC-MSC-derived exosomes attenuate hair follicle senescence and promote hair regeneration through the miR-21-5p/DKK2/Wnt/β-catenin/COL17A1 axis, providing a promising cell-free strategy for scalp rejuvenation.</p>","PeriodicalId":12448,"journal":{"name":"Frontiers in Cell and Developmental Biology","volume":"14 ","pages":"1807877"},"PeriodicalIF":4.6,"publicationDate":"2026-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13143841/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147835892","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":"Anti-fatigue mechanism of <i>Dendrobium officinale</i> pseudobulbs from different growth durations against chronic fatigue syndrome in mice and analysis of their active chemical components.","authors":"Minda Zhang, Haishen Li, Junhao Dai, Xiaotong Wang, Jian Sun, Jing Xu, Kang Ye, Chuanbao Wang, Long Cai, Zhian Wang, Qingsong Shao, Zhenhao Li","doi":"10.3389/fcell.2026.1797074","DOIUrl":"https://doi.org/10.3389/fcell.2026.1797074","url":null,"abstract":"<p><p>To investigate the differential efficacy of <i>Dendrobium officinale</i> pseudobulb alcohol extracts from varying growth durations against chronic fatigue syndrome (CFS) in mice, elucidate the underlying anti-CFS mechanisms, and identify the pharmacologically active components responsible. An ICR mouse model of CFS was established using the forced swimming test (FST). Behavioral characteristics, physiological phenotypes, biochemical parameters, and plasma metabolomics profiles were assessed. Concurrently, untargeted metabolomics and high-performance liquid chromatography (HPLC) were employed to analyze the chemical constituents of <i>D. officinale</i> pseudobulbs from different cultivation periods. Correlation analysis between the identified anti-CFS characteristic metabolites in plasma and the pseudobulb components was performed to predict the potential active ingredients against CFS in <i>D. officinale</i> pseudobulbs. Compared with the one-year-cultivated <i>D. officinale</i> extract (1DOE), the three-year-cultivated <i>D. officinale</i> extract (3DOE) significantly reduced anal temperature, prolonged forced swimming time, decreased liver index and plasma lactate dehydrogenase (LDH) levels, lowered cAMP levels and the cAMP/cGMP ratio, and mitigated renal inflammatory infiltration in model mice. Plasma metabolomic pathway analysis indicated that 3DOE extract alleviated energy metabolism dysregulation by enhancing energy metabolism and promoting oxidative utilization of fatty acids and proteins. Characteristic metabolites included arachidonic acid, L-5-oxoproline, pyroglutamic acid, D-(+)-malic acid, and PC (20:5/22:5). Correlation analysis between key metabolites and pseudobulb bioactive constituents revealed that flavonoids, polyphenols, lignans, terpenoids, and bibenzyls, which are significantly enriched in 3DOE, constitute the pharmacodynamic basis for the anti-CFS efficacy. These findings provide a scientific foundation for applying perennial <i>D. officinale</i> in the management of fatigue-related disorders, including CFS.</p>","PeriodicalId":12448,"journal":{"name":"Frontiers in Cell and Developmental Biology","volume":"14 ","pages":"1797074"},"PeriodicalIF":4.6,"publicationDate":"2026-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13143996/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147835907","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":"Modeling the spatiotemporal properties of crosstalk between RyR-mediated and IP₃R-mediated local Ca²⁺ release.","authors":"DeAnalisa C Jones, Eric A Sobie","doi":"10.3389/fcell.2026.1736729","DOIUrl":"https://doi.org/10.3389/fcell.2026.1736729","url":null,"abstract":"&lt;p&gt;&lt;p&gt;Ryanodine receptors (RyR) and IP&lt;sub&gt;3&lt;/sub&gt; receptors (IP&lt;sub&gt;3&lt;/sub&gt;R) are Ca&lt;sup&gt;2+&lt;/sup&gt; release channels expressed on the endoplasmic/sarcoplasmic reticulum (ER/SR) membrane in various cell types. Both the spatial localization and the distinct gating properties of these channels contribute to the diverse cellular functions controlled by intracellular Ca&lt;sup&gt;2+&lt;/sup&gt; signaling. It is known that both RyR2s and IP&lt;sub&gt;3&lt;/sub&gt;R2s are expressed on the SR membrane of ventricular cardiomyocytes and that the expression of IP&lt;sub&gt;3&lt;/sub&gt;R2s on the SR is increased in cardiac diseases such as heart failure (HF), and evidence that Ca&lt;sup&gt;2+&lt;/sup&gt; release through IP&lt;sub&gt;3&lt;/sub&gt;R2s can influence RyR2-mediated Ca&lt;sup&gt;2+&lt;/sup&gt; release in excitation-contraction coupling has been described. However, despite the suggested functional role for crosstalk between RyR2s and IP&lt;sub&gt;3&lt;/sub&gt;R2s, especially under pathologic conditions, most previous mathematical models of cardiomyocyte Ca&lt;sup&gt;2+&lt;/sup&gt; signaling have accounted for only RyR2s in isolation. We hypothesized that the combined effects of (1) fragmentation and dispersion of RyR2s within calcium release units (CRUs) and (2) increased expression of IP&lt;sub&gt;3&lt;/sub&gt;R2s that occur in HF promote pro-arrhythmic Ca&lt;sup&gt;2+&lt;/sup&gt; spark behavior, which may contribute to increased risk of arrhythmogenic Ca&lt;sup&gt;2+&lt;/sup&gt; wave formation and incidence of ventricular arrhythmias. We built a stochastic mathematical model of local SR Ca&lt;sup&gt;2+&lt;/sup&gt; release events-Ca&lt;sup&gt;2+&lt;/sup&gt; sparks-that incorporates both RyR2s and IP&lt;sub&gt;3&lt;/sub&gt;R2s. This model considers the spatial arrangement of RyR2s and IP&lt;sub&gt;3&lt;/sub&gt;R2s relative to one another based on published immunohistochemistry studies and the arrangement of RyR2s under HF and healthy control conditions based on super-resolution microscopy data. RyR2 and IP&lt;sub&gt;3&lt;/sub&gt;R2 gating are modeled based on single channel patch clamp studies which show that (1) RyR2 gating is stochastic and depends on local cytosolic [Ca&lt;sup&gt;2+&lt;/sup&gt;], JSR [Ca&lt;sup&gt;2+&lt;/sup&gt;], and allosteric coupling, (2) IP&lt;sub&gt;3&lt;/sub&gt;R2 gating is stochastic and depends primarily on local cytosolic [Ca&lt;sup&gt;2+&lt;/sup&gt;] and [IP&lt;sub&gt;3&lt;/sub&gt;], and the (3) RyR2 has a larger single channel Ca&lt;sup&gt;2+&lt;/sup&gt; current than the IP&lt;sub&gt;3&lt;/sub&gt;R2. Our simulations show that Ca&lt;sup&gt;2+&lt;/sup&gt; spark probability increases with increasing IP&lt;sub&gt;3&lt;/sub&gt;R2 expression in HF CRUs and IP&lt;sub&gt;3&lt;/sub&gt;R2 expression mitigates differences in mean duration of and mean total Ca&lt;sup&gt;2+&lt;/sup&gt; released during Ca&lt;sup&gt;2+&lt;/sup&gt; sparks observed in simulations in which HF is modeled as fragmentation and dispersion of RyR2s within CRUs alone. Overall, this mathematical modeling study suggests that increased IP&lt;sub&gt;3&lt;/sub&gt;R2 expression in the context of HF may contribute to pro-arrhythmic Ca&lt;sup&gt;2+&lt;/sup&gt; signaling via increased Ca&lt;sup&gt;2+&lt;/sup&gt; spark frequency but may also serve a compensatory function by countering changes in Ca&lt;sup&gt;2+&lt;/sup&gt; spark morphology tha","PeriodicalId":12448,"journal":{"name":"Frontiers in Cell and Developmental Biology","volume":"14 ","pages":"1736729"},"PeriodicalIF":4.6,"publicationDate":"2026-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13144025/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147835850","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":"Integrating single-cell and bulk RNA sequencing data reveals RGS4 as a functional driver in a proliferative subgroup of SF-1 lineage PitNETs.","authors":"Changxi Han, Qiuyue Fang, Bo Zhang, Ying Yuan, Can Xu, Jin Yang, Yangyang Wang, Mingjun Gao, Huan Xiong, Ruxiang Xu","doi":"10.3389/fcell.2026.1815682","DOIUrl":"https://doi.org/10.3389/fcell.2026.1815682","url":null,"abstract":"<p><strong>Introduction: </strong>The molecular determinants underlying the heterogeneity and proliferative behavior of Steroidogenic Factor-1 (SF-1) lineage Pituitary Neuroendocrine Tumors (PitNETs) remain insufficiently defined.</p><p><strong>Methods: </strong>We performed an integrated analysis of single-cell RNA sequencing (scRNA-seq) and bulk transcriptomic datasets from SF-1 lineage PitNETs to identify molecular subgroups and their defining biomarkers. The functional significance of the top candidate gene, Regulator of G-protein Signaling 4 (RGS4), was examined using gain- and loss-of-function approaches and pharmacological inhibition in pituitary adenoma cell lines. Mechanistic studies were conducted using protein interaction and stability assays.</p><p><strong>Results: </strong>We identified a previously unrecognized SF-1 lineage subgroup characterized by markedly elevated <i>RGS4</i> expression, which correlated with larger tumor size and higher MIB-1 proliferation index. Functional experiments demonstrated that <i>Rgs4</i> enhances tumor cell proliferation and inhibits apoptosis. Mechanistically, RGS4 promotes p53 ubiquitination, resulting in its destabilization and proteasomal degradation.</p><p><strong>Conclusion: </strong>This study defines a new SF-1 lineage PitNETs subgroup characterized by high-<i>RGS4</i> expression. RGS4 promotes tumor proliferation by destabilizing p53, highlighting the RGS4-p53 axis as a promising therapeutic target.</p>","PeriodicalId":12448,"journal":{"name":"Frontiers in Cell and Developmental Biology","volume":"14 ","pages":"1815682"},"PeriodicalIF":4.6,"publicationDate":"2026-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13144082/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147835858","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}