American journal of physiology. Cell physiology最新文献

{"title":"Single-cell transcriptomic analysis reveals alterations to cellular dynamics and paracrine signaling in radiation-induced muscle pathology.","authors":"Nicolás Collao, Emma B Johannsen, Jesper Just, Michael De Lisio","doi":"10.1152/ajpcell.00115.2025","DOIUrl":"10.1152/ajpcell.00115.2025","url":null,"abstract":"<p><p>Radiation therapy causes long-term skeletal muscle atrophy and fibrosis in juvenile cancer survivors. The mechanisms responsible for the skeletal muscle late effects of radiation therapy are not well-understood and have prevented the development of effective treatments. Using single-cell RNA sequencing (scRNA-seq), we characterize cellular dynamics and communication in a murine model of therapeutic radiation at 24 h and 56 days post-irradiation (post-IR). We detected changes in muscle stem (satellite) cells (MuSCs) characterized by an acute preservation of committed MuSCs and long-term relative depletion of deep quiescent MuSCs. A conserved senescence <i>Cdkn1a</i> signature was observed in all muscle-resident cells post-IR. Genes related to fibroblast proliferation were upregulated and a fibrotic and senescent transcriptome persisted in fibro-adipogenic progenitors (FAPs) post-IR. Intercellular communication analysis revealed FAPs as the primary contributor of extracellular matrix (ECM) and target of monocyte/macrophage-derived transforming growth factor (TGF)-β signaling post-IR through TGF-βR2 on FAPs. Together, our findings provide insights into the potential mechanisms and intercellular communication responsible for radiation-induced muscle atrophy and fibrosis.<b>NEW & NOTEWORTHY</b> This work describes, for the first time, the transcriptional changes occurring following radiation exposure in the skeletal muscle microenvironment using scRNA-seq technology. We revelated that FAPs exhibited a profibrotic and senescent transcriptome. Radiation exposure led to a conserved and persistent <i>Cdkn1a</i> gene signature and impairs intercellular communication, increasing TGF-βR2 signaling in FAPs. These findings uncover potential mechanisms and intercellular communication responsible for long-term muscle impairments post-radiation, offering new targets for therapeutic intervention.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C1995-C2012"},"PeriodicalIF":5.0,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143959998","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":"PCP protein Prickle 1 regulates Sertoli cell and testis function via cytoskeletal organization through the recruitment of multiple regulatory proteins.","authors":"Lingling Wang, Tiao Bu, Sheng Gao, Damin Yun, Hao Chen, C Yan Cheng, Fei Sun","doi":"10.1152/ajpcell.00861.2024","DOIUrl":"10.1152/ajpcell.00861.2024","url":null,"abstract":"<p><p>Prickle 1, an ortholog found in <i>Drosophila</i>, was localized at the Sertoli cell-spermatid interface consistent with its role of supporting the Vangl2 planar cell polarity (PCP), which is an integral membrane protein that creates the PCP protein complex of Vangl2 (Van Gogh-like 2)/Prickle1. Together with the asymmetrically localized transmembrane protein Frizzled (Fzd) and its unique adaptor proteins Disheveled (Dvl) and Inversin (Inv), Vangl2/Prickle1 and Fzd/Dvl/Inv are the two heterodimeric interacting PCP proteins between Sertoli cells and condensed spermatids to confer spermatid PCP across the plane of the seminiferous epithelium. Our initial intention was to examine if the distribution and expression of Prickle1 using a primary Sertoli cell in vitro model and Sprague-Dawley rats in vivo would mimic much of the earlier reported findings of Vangl2. Unexpectedly, these findings indicated that Prickle1 supported the PCP protein Vangl2; however, Prickle1 is also a multifunctional protein. First, Prickle1 knockdown (KD) by RNAi impeded Sertoli cell TJ function by perturbing the distribution of the BTB-associated proteins at the cell-cell interface, through disruption of the microtubule (MT) and actin cytoskeletal organization including their respective polymerization (and/or bundling) capability. Second, these findings were reproduced using an in vivo model of RNAi by KD of Prickle 1 in the testis. Third, using coimmunoprecipitation (Co-IP), Prickle 1 was found to interact with a host of adaptor proteins crucial to support not only PCP, such as Dvl, but also regulatory cytoskeletal proteins of MT and actin networks, including RhoA, Arp3, Cdc42, ZO-1, and β-catenin by immunoprecipitation-mass spectrometry (IP-MS) using the String Protein Interaction Tool.<b>NEW & NOTEWORTHY</b> This article was written based on results from a series of experiments to understand the function of planar cell polarity (PCP) protein Prickle 1 in the testis to support spermatogenesis. It was unexpectedly shown that Prickle1 was found to recruit several important regulatory proteins at the site where the Sertoli cell and condensed spermatids interact to modulate cytoskeletal functions of both actin and microtubule. These findings are important to both cell and molecular biologists.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C2032-C2056"},"PeriodicalIF":5.0,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143956569","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":"GLP-1 receptor agonists in the context of cancer: the road ahead.","authors":"Isabelle R Miousse","doi":"10.1152/ajpcell.00245.2025","DOIUrl":"10.1152/ajpcell.00245.2025","url":null,"abstract":"<p><p>A rapidly increasing proportion of the population in the United States is taking glucagon-like peptide-1 receptor agonists (GLP-1RAs) for type 2 diabetes or weight loss. Consequently, an increasing number of patients presenting with new cases of cancer also have a current prescription for GLP-1RAs. The impact of GLP-1RAs on metabolism is quite profound, and it is entirely reasonable to assume these agents are also very impactful on the metabolism of cancer cells, in addition to the general metabolism of the patient. Although these drugs are relatively recent on the market, the study of metabolism in cancer is a well-established field and we can make predictions about how GLP-1RAs will interface with cancer treatments. In fact, some evidence points to a possible neoadjuvant effect of these drugs for patients with cancer that would justify the initiation of GLP-1RAs to support therapy in a subset of patients. At the same time, there is a very present concern that drugs that induce weight loss may also precipitate the loss of muscle mass, cachexia, in patients. Here, we will provide an overview of the existing literature around diabetes and metabolism in the context of cancer and cachexia.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C1822-C1828"},"PeriodicalIF":5.0,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12109175/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143959390","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":"AAV1-CFTR preferentially transduces cysts and reduces cyst size in a mouse model of ADPKD.","authors":"Cristian Ciobanu, Liudmila Cebotaru","doi":"10.1152/ajpcell.00057.2025","DOIUrl":"https://doi.org/10.1152/ajpcell.00057.2025","url":null,"abstract":"<p><p>To overcome the challenges of developing a gene therapy for autosomal dominant polycystic kidney disease (ADPKD), we focused on the surface receptors expressed in cystic epithelia. Importantly, we detected altered localization in the cystic epithelium of wheat germ agglutinin, WGA, staining of sialic acids. Throughout the membrane of the cysts, we saw altered staining with <i>Maackia amurensis</i> lectin (MAL) or with <i>Sambucus nigra</i> lectin (SNL) that are specific for α2,3- and α2,6-<i>N</i>-linked sialic acids, respectively. Given that these sialic acid glycoproteins facilitate the transduction of adeno-associated virus 1 (AAV1), we injected 1-mo-old, <i>pkd1^{R3277C/R3277C}</i>, (RC/RC) ADPKD mice intraperitoneally with 2 × 10¹² particles/kg of AAV1 containing either a green fluorescent protein (GFP) vector or a truncated cystic fibrosis transmembrane conductance regulator (CFTR) vector, Δ27-264-CFTR. Two months after treatment, the cyst area and size were significantly lower in the CFTR vector-treated mice compared with those untreated and those receiving the GFP. We detected vector genomes and mRNA expression only in their corresponding CFTR vector- or GFP vector-treated mice. We observed co-staining for GFP and CFTR immunofluorescence with either the Na⁺/H⁺ exchanger or epithelial Na⁺ channel, indicating proximal tubule or collecting duct expression, respectively. Expression of GFP and CFTR protein expression above background levels was detected. CFTR immunofluorescence was increased in the basolateral membrane after CFTR vector instillation. Finally, these data suggest that cysts are prime targets for AAV1 gene therapy and offer an exciting prospect for ADPKD gene therapy.<b>NEW & NOTEWORTHY</b> Current therapies for ADPKD involve treatment of the symptoms. A direct approach would involve a gene therapy. Here we show AAV1 is tropic for cystic epithelia, which have abundant expression of sialic acid resides known to enhance AAV1 transduction. We show that a CFTR-based vector can reduce cyst size, suggesting that it may be therapeutic. These data suggest that cysts are prime targets for AAV1 and offer an exciting prospect for ADPKD gene therapy.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":"328 6","pages":"C1783-C1792"},"PeriodicalIF":5.0,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143963791","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":"Decorin the antifibrotic proteoglycan and its progression in therapy.","authors":"Kornélia Baghy, Helga Szakadáti, Ilona Kovalszky","doi":"10.1152/ajpcell.01075.2024","DOIUrl":"10.1152/ajpcell.01075.2024","url":null,"abstract":"<p><p>Fibrosis, which underlies numerous chronic diseases, is characterized by excessive extracellular matrix (ECM) accumulation, resulting in disrupted tissue architecture. Decorin, a small leucine-rich proteoglycan synthesized primarily by fibroblasts and myoblasts, has emerged as a potent antifibrotic agent mainly by inhibiting transforming growth factor-β (TGF-β), which is a major driver of fibrosis in various tissues and organs such as the heart, eyes, skin, liver, muscle, etc. Numerous therapeutic applications of decorin showcase its ability to reduce fibrosis and improve tissue function. Advances in treatments utilizing recombinant protein, gene-delivery systems, and biomaterials, such as decorin-loaded hydrogels, have demonstrated decorin's potential to improve localized and systemic fibrosis therapies. This review discusses recent advances in decorin's antifibrotic potential and its therapeutic applications.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C1853-C1865"},"PeriodicalIF":5.0,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143966197","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":"Molecular determinants of [Formula: see text] and cation transport in the human cation-dependent Cl^-/[Formula: see text] exchanger AE4.","authors":"Marcelo A Catalán, Lisandra Flores-Aldama, Fernanda Fernández, Daniel Bustos, Natalia Apablaza, Ailen Hidalgo, Yuliet Mazola, Ella Matamala, Li Yo Kao, Ira Kurtz, Carlos Spichiger, José M Sarmiento, Sebastián Brauchi, Wendy González, Leandro Zúñiga, Gaspar Peña-Münzenmayer","doi":"10.1152/ajpcell.00346.2024","DOIUrl":"10.1152/ajpcell.00346.2024","url":null,"abstract":"<p><p>The [Formula: see text] transporter AE4 (<i>SLC4A9</i>) plays a role in NaCl reabsorption and pH sensing in the kidney, and Cl^--dependent fluid secretion in salivary glands. Sharing functional features with other Cl^-/[Formula: see text] exchangers and Na⁺-[Formula: see text] cotransporters, it has been proposed that AE4 mediates Cl^-/cation-[Formula: see text] exchange. Our sequence alignments and molecular dynamics (MD) analysis showed that three residues, reported as critical for transport activity in other SLC4 transporters, are conserved in AE4, suggesting similarities in their ion transport mechanism. Site-directed mutagenesis and further functional experiments showed that two out of the three conserved residues (D709 and T448) are functionally relevant, but in contrast to other SLC4 transporters, where transport was almost completely abolished, AE4 mutants conserved about 50% of transport activity. In addition, alanine scanning showed that S446A and T756A decreased transport by nearly 30%. Consistent with an additive effect of mutations at positions T756 and T448, the double mutant T756A-T448I completely abolished transport in the presence of extracellular Na⁺ but interestingly exhibited anion transporter activity in the presence of K⁺ as the main extracellular cation. MD simulations revealed that the [Formula: see text] and cation coordination site is at the interface between the transmembrane segments TM3-TM10. The interaction network was importantly disrupted in the double mutant in the presence of Na⁺, but it is partially conserved in the presence of K⁺, suggesting differences in the cation coordination. In summary, we identified the putative cation coordination site of AE4 and the critical functional role of residues T756 and T448 in its transport cycle.<b>NEW & NOTEWORTHY</b> AE4 is a [Formula: see text] transporter that is important for electrolyte transport and pH regulation in epithelia, which has been proposed to mediate Cl^-/cation-[Formula: see text] exchange. However, critical residues sustaining transport activity are not known. In this study, we show that AE4 can coordinate [Formula: see text] and Na⁺ or K⁺ at the TM3-TM10 interface and that residues T448 and T756 are crucial for cation binding and transport cycle.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C2070-C2084"},"PeriodicalIF":5.0,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143966229","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":"Are you listening: cellular signaling in ECM-driven diseases.","authors":"Alexander Nyström","doi":"10.1152/ajpcell.00337.2025","DOIUrl":"10.1152/ajpcell.00337.2025","url":null,"abstract":"","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C1829-C1830"},"PeriodicalIF":5.0,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143953456","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":"Interleukin-6 from the adipose secretome potentiates differentiation of adipose progenitors through the activation of redox signaling.","authors":"Jessica L Wager, Larissa G Baker, Taylor B Scheidl, Sophie Z Yonan, Pina Colarusso, Daniel Young, Antoine Dufour, Jennifer A Thompson","doi":"10.1152/ajpcell.00024.2025","DOIUrl":"10.1152/ajpcell.00024.2025","url":null,"abstract":"<p><p>Under obesogenic conditions, it is thought that a signal arising from the adipose microenvironment triggers differentiation of adipose progenitor cells (APCs); yet the identity and source of this signal remain unknown. Redox signaling was shown to influence adipogenesis in primary murine APCs treated with pharmacological agents to manipulate the levels of reactive oxygen species (ROS). Increased generation of superoxide ([Formula: see text]) and hydrogen peroxide (H₂O₂) via redox cyclers amplified APC differentiation, while differentiation was blunted with ROS scavengers and antioxidants. Protein was concentrated from conditioned media of adipose tissue explants cultured ex vivo to capture secreted factors. Differentiation was enhanced in APCs cultured in the presence of the adipose protein secretome, an effect that was diminished with scavenging of ROS and amplified when the secretome was collected from mice fed a high-fat diet. Proteomic analysis revealed that the adipose secretome from animals on a high-fat diet was enriched in pathways involved in immune cell responses and contained higher levels of cytokines, including interleukin 6 (IL-6). A multiplex assay confirmed higher IL-6, which was predicted as a central regulator of differential levels of secretome proteins. Exposure of APCs to IL-6 increased adipogenesis, while treatment of APCs with an IL-6 blocking antibody diminished the adipogenic effect of the adipose secretome. Together, these findings substantiate a role for redox signaling in the regulation of adipogenesis and identify IL-6 as a potential secreted factor that may mediate activation of adipogenesis via ROS generation under obesogenic conditions.<b>NEW & NOTEWORTHY</b> This study identified IL-6 as an adipose-secreted factor that is increased in obesity and potentiates differentiation of APCs. Redox signaling is involved in APC differentiation and mediates the proadipogenic effect of IL-6. Thus, IL-6 may be a paracrine regulator of APC differentiation in the setting of obesity.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":"328 6","pages":"C1730-C1742"},"PeriodicalIF":5.0,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143962568","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":"Physical activity and other modifiers of extracellular matrix dynamics in healthy and diseased tendon tissue: focus on in vivo techniques.","authors":"Benjamin Rosborg, Michael Kjaer, Ann Damgaard","doi":"10.1152/ajpcell.01042.2024","DOIUrl":"10.1152/ajpcell.01042.2024","url":null,"abstract":"<p><p>Tendons have traditionally been considered largely metabolically inert, and little research has focused on tendon matrix dynamics. In the past few decades, the study of tendon extracellular matrix dynamics in humans has progressed immensely as new methods have been used to investigate long-term tissue remodeling and more acute changes in the turnover of extracellular matrix in tendon tissue. The number of human in vivo trials has increased, and new exciting fields of research in modifiers of tissue dynamics have advanced tendon research and provided new insight. This paper reviews the current knowledge of tendon extracellular matrix dynamics in healthy and diseased tissues. Furthermore, we review the response of various factors such as loading, unloading, exogenous growth factors, and aging. Physical activity and growth factors stimulate protein synthesis in a minor fraction of the adult human tendon, whereas inactivity reduces synthesis and increases breakdown of proteins in tendon. The influence of physical activity level seems to surpass the impact of aging per se on tissue turnover in tendon. A comprehensive understanding of tendon tissue extracellular matrix dynamics and its adaptation to modifiers is crucial for establishing a foundation for tendon injury prevention, treatment, and rehabilitation.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C2085-C2094"},"PeriodicalIF":5.0,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144075436","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":"Obesity and type 2 diabetes mellitus: insights from skeletal muscle extracellular matrix remodeling.","authors":"Linda Wu, Dawn K Coletta","doi":"10.1152/ajpcell.00154.2024","DOIUrl":"https://doi.org/10.1152/ajpcell.00154.2024","url":null,"abstract":"<p><p>Obesity and type 2 diabetes mellitus (T2DM) are metabolic diseases at epidemic proportions. The economic burden for these diseases is at an all-time high, and as such, there is an urgent need for advancements in identifying targets for treating these complex disorders. The extracellular matrix (ECM), comprising collagen, fibronectin, laminin, elastin, and proteoglycan, surrounds skeletal muscles and plays a critical role in maintaining tissue homeostasis by providing structural support and facilitating cell-to-cell communication. Disruption of the ECM signaling results in changes to its micro/macroenvironment, thereby modifying tissue homeostasis. Skeletal muscle ECM remodeling has been shown to be associated with insulin resistance, an underlying feature of obesity and T2DM. This narrative review explores the critical components of skeletal muscle ECM and its accumulation and remodeling in metabolic diseases. In addition, we discuss potential treatments to mitigate the effects of ECM remodeling in skeletal muscle. We conclude that targeting ECM remodeling in skeletal muscle represents a promising yet underexplored therapeutic avenue in the management of metabolic disorders.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":"328 6","pages":"C1752-C1763"},"PeriodicalIF":5.0,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143955952","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}