Biology of the Cell最新文献

{"title":"Label-free 3D characterization of cardiac fibrosis in muscular dystrophy using SHG imaging of cleared tissue","authors":"Julien Pichon,&nbsp;Mireille Ledevin,&nbsp;Thibaut Larcher,&nbsp;Frédéric Jamme,&nbsp;Karl Rouger,&nbsp;Laurence Dubreil","doi":"10.1111/boc.202100056","DOIUrl":"10.1111/boc.202100056","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background information</h3>\u0000 \u0000 <p>Duchenne muscular dystrophy (DMD) is a neuromuscular disease caused by mutations in the gene encoding dystrophin. It leads to repeated cycles of muscle fiber necrosis and regeneration and progressive replacement of fibers by fibrotic and adipose tissue, with consequent muscle weakness and premature death. Fibrosis and, in particular, collagen accumulation are important pathological features of dystrophic muscle. A better understanding of the development of fibrosis is crucial to enable better management of DMD. Three-dimensional (3D) characterization of collagen organization by second harmonic generation (SHG) microscopy has already proven a highly informative means of studying the fibrotic network in tissue.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Here, we combine for the first-time tissue clearing with SHG microscopy to characterize in depth the 3D cardiac fibrosis network from DMD^mdx rat model. Heart sections (1-mm-thick) from 1-year-old wild-type (WT) and DMD^mdx rats were cleared using the CUBIC protocol. SHG microscopy revealed significantly greater collagen deposition in DMD^mdx versus WT sections. Analyses revealed a specific pattern of SHG⁺ segmented objects in DMD^mdx cardiac muscle, characterized by a less elongated shape and increased density. Compared with the observed alignment of SHG⁺ collagen fibers in WT rats, profound fiber disorganization was observed in DMD^mdx rats, in which we observed two distinct SHG⁺ collagen fiber profiles, which may reflect two distinct stages of the fibrotic process in DMD.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion and significance</h3>\u0000 \u0000 <p>The current work highlights the interest to combine multiphoton SHG microscopy and tissue clearing for 3D fibrosis network characterization in label free organ. It could be a relevant tool to characterize the fibrotic tissue remodeling in relation to the disease progression and/or to evaluate the efficacy of therapeutic strategies in preclinical studies in DMD model or others fibrosis-related cardiomyopathies diseases.</p>\u0000 </section>\u0000 </div>","PeriodicalId":8859,"journal":{"name":"Biology of the Cell","volume":"114 3","pages":"91-103"},"PeriodicalIF":2.7,"publicationDate":"2021-12-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39772240","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Human breast tumor derived endothelial cells exhibit distinct biological properties","authors":"Mangala Hegde,&nbsp;Sharath Mohan Bhat,&nbsp;Kanive Parashiva Guruprasad,&nbsp;Rajasekhar Moka,&nbsp;Lingadakai Ramachandra,&nbsp;Kapaettu Satyamoorthy,&nbsp;Manjunath B. Joshi","doi":"10.1111/boc.202100015","DOIUrl":"10.1111/boc.202100015","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background Information</h3>\u0000 \u0000 <p>Excessive angiogenesis characterized by leaky, tortuous, and chaotic vasculature is one of the hallmarks of cancers and is significantly correlated to poor prognosis. Disorganized angiogenesis leads to poor perfusion of anti-cancer drugs and limits access to immune cells. Hence, impeding angiogenesis is one of the attractive therapeutic targets to inhibit progression and metastasis in several solid tumors including breast.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>We have developed a robust and reproducible method for isolating and ex vivo culture of endothelial cells (EC) derived from non-malignant (Endo-N) and malignant (Endo-T) part from clinically characterized human breast tumors. RT-PCR and immunoblotting analysis indicated that these cells exhibited expression of endothelial specific genes such as PECAM-1 (CD31), Endoglin (CD105), eNOS, VE-cadherin, VCAM1, and MCAM. Vasculogenic mimicry and contamination of progenitor EC recruited in tumors was ruled out by absence of CD133 expression and normal karyotype. Both the cell types showed stable expression of CD31 and CD105 up to seven passages. Furthermore, compared to Endo-N cells, Endo-T cells showed (a) constitutively increased proliferation marked by nearly 36% of cells in mitotic phase, (b) requirement of glutamine for cell survival, (c) pro-migratory phenotype, (d) produced increased number of sprouts in 3D cultures, and (e) resistance to sorafenib.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Tumor derived EC showed distinct biological properties compared to normal breast EC.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Significance</h3>\u0000 \u0000 <p>Our method for isolating endothelial cell types from human breast tumors may be explored to (a) understand cellular and molecular mechanisms, (b) screen anti-angiogenic molecules, and (c) formulate organoid cultures to develop personalized medicine facilitating better clinical management of breast cancers.</p>\u0000 </section>\u0000 </div>","PeriodicalId":8859,"journal":{"name":"Biology of the Cell","volume":"114 2","pages":"73-85"},"PeriodicalIF":2.7,"publicationDate":"2021-11-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39872741","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"How palmitoylation affects trafficking and signaling of membrane receptors","authors":"Maxime Jansen,&nbsp;Bruno Beaumelle","doi":"10.1111/boc.202100052","DOIUrl":"10.1111/boc.202100052","url":null,"abstract":"<p>S-acylation (or palmitoylation) is a reversible post-translational modification (PTM) that modulates protein activity, signalization and trafficking. Palmitoylation was found to significantly impact the activity of various membrane receptors involved in either pathogen entry, such as CCR5 (for HIV) and anthrax toxin receptors, cell proliferation (epidermal growth factor receptor), cardiac function (β-Adrenergic receptor), or synaptic function (AMPA receptor). Palmitoylation of these membrane receptors indeed affects not only their internalization, localization, and activation, but also other PTMs such as phosphorylation. In this review, we discuss recent results showing how palmitoylation differently affects the biology of these membrane receptors.</p>","PeriodicalId":8859,"journal":{"name":"Biology of the Cell","volume":"114 2","pages":"61-72"},"PeriodicalIF":2.7,"publicationDate":"2021-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39592692","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Issue Information","authors":"","doi":"10.1111/boc.202170022","DOIUrl":"https://doi.org/10.1111/boc.202170022","url":null,"abstract":"","PeriodicalId":8859,"journal":{"name":"Biology of the Cell","volume":" ","pages":""},"PeriodicalIF":2.7,"publicationDate":"2021-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"46117242","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Endocytosis and stress: From mechanisms to cellular physiology.","authors":"Sébastien Léon","doi":"10.1111/boc.202100072","DOIUrl":"https://doi.org/10.1111/boc.202100072","url":null,"abstract":"This issue presents a series of articles and reviews on the theme “Endocytosis and stress.” The purpose of this issue was to cover various aspects of the functions of endocytosis, but also in a variety of model organisms to highlight how this conserved process has been exploited throughout evolution. A series of reviews highlight connections between endocytosis and the properties of the extracellular environment, including signaling molecules, nutrient availability, or biophysical constraints, as well as the importance of endocytosis in cellular function, adaptation, and pathologies. The plethora of cellular functions regulated by endocytosis is well discussed by Giangreco et al. (2021) who provide a series of examples illustrating the various functions of endocytic proteins in cellular physiology, and the pathologies derived from their malfunction. This includes the role of adaptor proteins in clathrinmediated endocytosis (CME) and non-clathrin-mediated endocytosis (NCE), how this regulates signaling pathways, and the links with tumorigenesis.Two reviews then detail the connections between endocytosis and the regulation of signaling pathways. Wu et al. (2021) focus on the mechanisms by which Wnt signaling, a key pathway in development and morphogenesis in animals, is regulated by endocytosis and endosomal trafficking. They notably highlight work in Caenorhabditis elegans on the involvement in Wnt signaling and stress response. Seib and Klein (2021) then discuss the role of endocytosis in the activation of Notch signaling. They mention the importance of endocytosis in generating pulling forces leading to Notch cleavage, a crucial step in Notch pathway activation, but also additional functions in the recycling of Notch ligands. The interplay between membrane tension and CME is carefully reviewed by Djakbarova et al. (2021). The importance of membrane tension in physiological processes such as cell division, migration, or spreading is also underscored. In their monograph, the authors detail how membrane tension is established, regulated, and how this regulates CME. Two additional reviews focus on the regulation of nutrient transporters by endocytosis. Ivanov and Vert (2021) describe the exquisite molecular mechanisms by which","PeriodicalId":8859,"journal":{"name":"Biology of the Cell","volume":"113 11","pages":"439-440"},"PeriodicalIF":2.7,"publicationDate":"2021-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39516685","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Direct measurement of near-nano-Newton forces developed by self-organizing actomyosin fibers bound α-catenin.","authors":"Surabhi Sonam,&nbsp;Clémence Vigouroux,&nbsp;Antoine Jégou,&nbsp;Guillaume Romet-Lemonne,&nbsp;Christophe Le Clainche,&nbsp;Benoit Ladoux,&nbsp;René Marc Mège","doi":"10.1111/boc.202100014","DOIUrl":"https://doi.org/10.1111/boc.202100014","url":null,"abstract":"<p><strong>Background information: </strong>Actin cytoskeleton contractility plays a critical role in morphogenetic processes by generating forces that are then transmitted to cell-cell and cell-ECM adhesion complexes. In turn, mechanical properties of the environment are sensed and transmitted to the cytoskeleton at cell adhesion sites, influencing cellular processes such as cell migration, differentiation and survival. Anchoring of the actomyosin cytoskeleton to adhesion sites is mediated by adaptor proteins such as talin or α-catenin that link F-actin to transmembrane cell adhesion receptors, thereby allowing mechanical coupling between the intracellular and extracellular compartments. Thus, a key issue is to be able to measure the forces generated by actomyosin and transmitted to the adhesion complexes. Approaches developed in cells and those probing single molecule mechanical properties of α-catenin molecules allowed to identify α-catenin, an F-actin binding protein which binds to the cadherin complexes as a major player in cadherin-based mechanotransduction. However, it is still very difficult to bridge intercellular forces measured at cellular levels and those measured at the single-molecule level.</p><p><strong>Results: </strong>Here, we applied an intermediate approach allowing reconstruction of the actomyosin-α-catenin complex in acellular conditions to probe directly the transmitted forces. For this, we combined micropatterning of purified α-catenin and spontaneous actomyosin network assembly in the presence of G-actin and Myosin II with microforce sensor arrays used so far to measure cell-generated forces.</p><p><strong>Conclusions: </strong>Using this method, we show that self-organizing actomyosin bundles bound to micrometric α-catenin patches can apply near-nano-Newton forces.</p><p><strong>Significance: </strong>Our results pave the way for future studies on molecular/cellular mechanotransduction and mechanosensing.</p>","PeriodicalId":8859,"journal":{"name":"Biology of the Cell","volume":"113 11","pages":"441-449"},"PeriodicalIF":2.7,"publicationDate":"2021-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39205106","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Bioengineering methods for organoid systems","authors":"Jad Saleh,&nbsp;Barbara Mercier,&nbsp;Wang XI","doi":"10.1111/boc.202000119","DOIUrl":"10.1111/boc.202000119","url":null,"abstract":"<p>Organoids have been widely used in fundamental, biomimetic, and therapeutic studies. These multicellular systems form via cell-autonomous self-organization where a cohort of stem cells undergoes in vivo-like proliferation, differentiation, and morphogenesis. They also recapitulate a series of physiological cell organization, complexity and functions that are untouchable by conventional bio-model systems using immortal cell lines. However, the development of organoids is often not easily controlled and their shape and size are yet fully physiological. Recent research has demonstrated that multiple bioengineering tools could be harnessed to control important internal and external cues that dictate stem cell behavior and stem-cell based organoid development. In this review, we introduce the current development of organoid systems and their potentials, as well as their limitations that impede their further utility in research and clinical fields. In comparison to conventional autonomous organoid system, we then review bioengineering approaches that offer improved control over organoid growth and development. We focus on the genetic editing tools that allow the program of build-in responses and phenotypes for organoid systems with enhanced physiological relevance. We also highlight the advances in bioengineering methods to modify cellular external milieus to generate desirable cell composition, 3D micro-architectures, and complex microfluidic systems. We conclude that the emerging biomimetic methods that employ multidisciplinary approaches could prevail in the future development of organoid systems.</p>","PeriodicalId":8859,"journal":{"name":"Biology of the Cell","volume":"113 12","pages":"475-491"},"PeriodicalIF":2.7,"publicationDate":"2021-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39464227","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Alpha-arrestins Aly1/Art6 and Aly2/Art3 regulate trafficking of the glycerophosphoinositol transporter Git1 and impact phospholipid homeostasis","authors":"Benjamin P. Robinson,&nbsp;Sarah Hawbaker,&nbsp;Annette Chiang,&nbsp;Eric M. Jordahl,&nbsp;Sanket Anaokar,&nbsp;Alexiy Nikiforov,&nbsp;Ray W. Bowman II,&nbsp;Philip Ziegler,&nbsp;Ceara K. McAtee,&nbsp;Jana Patton-Vogt,&nbsp;Allyson F. O'Donnell","doi":"10.1111/boc.202100007","DOIUrl":"10.1111/boc.202100007","url":null,"abstract":"&lt;div&gt;\u0000 \u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Background information&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Phosphatidylinositol (PI) is an essential phospholipid, critical to membrane bilayers. The complete deacylation of PI by B-type phospholipases produces intracellular and extracellular glycerophosphoinositol (GPI). Extracellular GPI is transported into the cell via Git1, a member of the Major Facilitator Superfamily of transporters at the yeast plasma membrane. Internalized GPI is degraded to produce inositol, phosphate and glycerol, thereby contributing to these pools. &lt;i&gt;GIT1&lt;/i&gt; gene expression is controlled by nutrient balance, with phosphate or inositol starvation increasing &lt;i&gt;GIT1&lt;/i&gt; expression to stimulate GPI uptake. However, less is known about control of Git1 protein levels or localization.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Results&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;We find that the α-arrestins, an important class of protein trafficking adaptor, regulate Git1 localization and this is dependent upon their interaction with the ubiquitin ligase Rsp5. Specifically, α-arrestin Aly2 stimulates Git1 trafficking to the vacuole under basal conditions, but in response to GPI-treatment, either Aly1 or Aly2 promote Git1 vacuole trafficking. Cell surface retention of Git1, as occurs in &lt;i&gt;aly1&lt;/i&gt;∆ &lt;i&gt;aly2&lt;/i&gt;∆ cells, is linked to impaired growth in the presence of exogenous GPI and results in increased uptake of radiolabeled GPI, suggesting that accumulation of GPI somehow causes cellular toxicity. Regulation of α-arrestin Aly1 by the protein phosphatase calcineurin improves steady-state and substrate-induced trafficking of Git1, however, calcineurin plays a larger role in Git1 trafficking beyond regulation of α-arrestins. Interestingly, loss of Aly1 and Aly2 increased phosphatidylinositol-3-phosphate on the limiting membrane of the vacuole, and this was further exacerbated by GPI addition, suggesting that the effect is partially linked to Git1. Loss of Aly1 and Aly2 leads to increased incorporation of inositol label from [&lt;sup&gt;3&lt;/sup&gt;H]-inositol-labelled GPI into PI, confirming that internalized GPI influences PI balance and indicating a role for the a-arrestins in this regulation.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Conclusions&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;The α-arrestins Aly1 and Aly2 are novel regulators of Git1 trafficking with previously unanticipated roles in controlling phospholipid distribution and balance.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Significance&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;To our knowledge, this is the first example of α-arrestin regulation of phosphatidyliniositol-3-phosphate levels. In future studies it will be exciting to determine if other α-arrestins similarly alter PI and PIPs to change the cellular landscape.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 ","PeriodicalId":8859,"journal":{"name":"Biology of the Cell","volume":"114 1","pages":"3-31"},"PeriodicalIF":2.7,"publicationDate":"2021-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/boc.202100007","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39450052","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A new pancreatic adenocarcinoma-derived organoid model of acquired chemoresistance to FOLFIRINOX: First insight of the underlying mechanisms","authors":"Elsa Hadj Bachir,&nbsp;Charles Poiraud,&nbsp;Sonia Paget,&nbsp;Nicolas Stoup,&nbsp;Soumaya El Moghrabi,&nbsp;Belinda Duchêne,&nbsp;Nathalie Jouy,&nbsp;Antonino Bongiovanni,&nbsp;Meryem Tardivel,&nbsp;Louis-Bastien Weiswald,&nbsp;Marie Vandepeutte,&nbsp;César Beugniez,&nbsp;Fabienne Escande,&nbsp;Emmanuelle Leteurtre,&nbsp;OrgaRES consortium,&nbsp;Laurent Poulain,&nbsp;Chann Lagadec,&nbsp;Pascal Pigny,&nbsp;Nicolas Jonckheere,&nbsp;Florence Renaud,&nbsp;Stephanie Truant,&nbsp;Isabelle Van Seuningen,&nbsp;Audrey Vincent","doi":"10.1111/boc.202100003","DOIUrl":"10.1111/boc.202100003","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background Information</h3>\u0000 \u0000 <p>Although improvements have been made in the management of pancreatic adenocarcinoma (PDAC) during the past 20 years, the prognosis of this deadly disease remains poor with an overall 5-year survival under 10%. Treatment with FOLFIRINOX, a combined regimen of 5-fluorouracil, irinotecan (SN-38) and oxaliplatin, is nonetheless associated with an excellent initial tumour response and its use has allowed numerous patients to go through surgery while their tumour was initially considered unresectable. These discrepancies between initial tumour response and very low long-term survival are the consequences of rapidly acquired chemoresistance and represent a major therapeutic frontier. To our knowledge, a model of resistance to the combined three drugs has never been described due to the difficulty of modelling the FOLFIRINOX protocol both in vitro and in vivo. Patient-derived tumour organoids (PDO) are the missing link that has long been lacking in the wide range of epithelial cancer models between 2D adherent cultures and in vivo xenografts. In this work we sought to set up a model of PDO with resistance to FOLFIRINOX regimen that we could compare to the paired naive PDO.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>We first extrapolated physiological concentrations of the three drugs using previous pharmacodynamics studies and bi-compartmental elimination models of oxaliplatin and SN-38. We then treated PaTa-1818x naive PDAC organoids with six cycles of 72 h-FOLFIRINOX treatment followed by 96 h interruption. Thereafter, we systematically compared treated organoids to PaTa-1818x naive organoids in terms of growth, proliferation, viability and expression of genes involved in cancer stemness and aggressiveness.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>We reproductively obtained resistant organoids FoxR that significantly showed less sensitivity to FOLFORINOX treatment than the PaTa-1818x naive organoids from which they were derived. Our resistant model is representative of the sequential steps of chemoresistance observed in patients in terms of growth arrest (proliferation blockade), residual disease (cell quiescence/dormancy) and relapse.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Significance</h3>\u0000 \u0000 <p>To our knowledge, this is the first genuine in vitro model of resistance to the three drugs in combined therapy. This new PDO model will be a great asset for the discovery of acquired chemoresistance mechanisms, knowledge that is mandatory before offering new therapeutic strategies for pancreatic cancer.</p>\u0000 </section>\u0000 </div>","PeriodicalId":8859,"journal":{"name":"Biology of the Cell","volume":"114 1","pages":"32-55"},"PeriodicalIF":2.7,"publicationDate":"2021-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/boc.202100003","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39447323","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Decreased proliferation of aged rat beta cells corresponds with enhanced expression of the cell cycle inhibitor p27KIP1","authors":"Talon J. Aitken,&nbsp;Jacqueline E. Crabtree,&nbsp;Daelin M. Jensen,&nbsp;Kavan H. Hess,&nbsp;Brennan R. Leininger,&nbsp;Jeffery S. Tessem","doi":"10.1111/boc.202100035","DOIUrl":"10.1111/boc.202100035","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Over 400 million people are diabetic. Type 1 and type 2 diabetes are characterized by decreased functional β-cell mass and, consequently, decreased glucose-stimulated insulin secretion. A potential intervention is transplantation of β-cell containing islets from cadaveric donors. A major impediment to greater application of this treatment is the scarcity of transplant-ready β-cells. Therefore, inducing β-cell proliferation ex vivo could be used to expand functional β-cell mass prior to transplantation. Various molecular pathways are sufficient to induce proliferation of young β-cells; however, aged β-cells are refractory to these proliferative signals. Given that the majority of cadaveric donors fit an aged demographic, defining the mechanisms that impede aged β-cell proliferation is imperative.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>We demonstrate that aged rat (5-month-old) β-cells are refractory to mitogenic stimuli that otherwise induce young rat (5-week-old) β-cell proliferation. We hypothesized that this change in proliferative capacity could be due to differences in cyclin-dependent kinase inhibitor expression. We measured levels of p16^INK4a, p15^INK4b, p18^INK4c, p19^INK4d, p21^CIP1, p27^KIP1 and p57^KIP2 by immunofluorescence analysis. Our data demonstrates an age-dependent increase of p27^KIP1 in rat β-cells by immunofluorescence and was validated by increased p27^KIP1 protein levels by western blot analysis. Interestingly, HDAC1, which modulates the p27^KIP1 promoter acetylation state, is downregulated in aged rat islets. These data demonstrate increased p27^KIP1 protein levels at 5 months of age, which may be due to decreased HDAC1 mediated repression of p27^KIP1 expression.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Significance</h3>\u0000 \u0000 <p>As the majority of transplant-ready β-cells come from aged donors, it is imperative that we understand why aged β-cells are refractory to mitogenic stimuli. Our findings demonstrate that increased p27^KIP1 expression occurs early in β-cell aging, which corresponds with impaired β-cell proliferation. Furthermore, the correlation between HDAC1 and p27 levels suggests that pathways that activate HDAC1 in aged β-cells could be leveraged to decrease p27^KIP1 levels and enhance β-cell proliferation.</p>\u0000 </section>\u0000 </div>","PeriodicalId":8859,"journal":{"name":"Biology of the Cell","volume":"113 12","pages":"507-521"},"PeriodicalIF":2.7,"publicationDate":"2021-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1111/boc.202100035","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39436553","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}