Article
Biochemistry & Molecular Biology
Lisa W. Rodenburg, Livia Delpiano, Violeta Railean, Raquel Centeio, Madalena C. Pinto, Shannon M. A. Smits, Isabelle S. van der Windt, Casper F. J. van Hugten, Sam F. B. van Beuningen, Remco N. P. Rodenburg, Cornelis K. van der Ent, Margarida D. Amaral, Karl Kunzelmann, Michael A. Gray, Jeffrey M. Beekman, Gimano D. Amatngalim
Summary: This study identified 12 FDA-approved drugs that can induce CFTR-independent fluid secretion through a medium-throughput screening of nasal CF airway epithelial organoids. The findings provide a new perspective for the treatment of CF patients.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Multidisciplinary Sciences
Lisa W. Rodenburg, Mieke Metzemaekers, Isabelle S. van der Windt, Shannon M. A. Smits, Loes A. den Hertog-Oosterhoff, Evelien Kruisselbrink, Jesse E. Brunsveld, Sabine Michel, Karin M. de Winter-de Groot, Cornelis K. van der Ent, Ralph Stadhouders, Jeffrey M. Beekman, Gimano D. Amatngalim
Summary: This study reveals that nasal and bronchial epithelial cells exhibit intrinsic differences in cell culture, which may impact the functioning of epithelial cells in cystic fibrosis patients. By comparing differentiated nasal and bronchial epithelial cells, specific transcription factors were identified, and differences in fluid secretion capacity were linked to ciliated cell differentiation. These findings contribute to understanding the effects of tissue-specific features on upper and lower respiratory disease development in cystic fibrosis.
SCIENTIFIC REPORTS
(2023)
Article
Biochemical Research Methods
Lisa W. Rodenburg, Isabelle S. van der Windt, Henriette H. M. Dreyer, Shannon M. A. Smits, Loes A. den Hertog-Oosterhoff, Ellen M. Aarts, Jeffrey M. Beekman, Gimano D. Amatngalim
Summary: We propose a protocol for generating organoids from ALI-differentiated nasal epithelia, which can be used as a cystic fibrosis disease model in the CFTR-dependent FIS assay. We provide step-by-step instructions for the isolation, expansion, and cryostorage of basal progenitor cells derived from nasal brushings, as well as their differentiation in ALI cultures. Additionally, we describe the conversion of differentiated epithelial fragments into organoids for CFTR function validation and modulator response testing. For complete details, please refer to Amatngalim et al.
Article
Engineering, Biomedical
Hui Chen, Zhuhao Wu, Zhiyi Gong, Yu Xia, Juan Li, Liang Du, Yuanzheng Zhang, Xiangyang Gao, Zhou Fan, Hang Hu, Qun Qian, Zhao Ding, Shishang Guo
Summary: A testing system called acoustically bioprinted patient-derived microtissues (PDMs) is reported, which can model cancer invasion and predict treatment response in individual patients with colorectal cancer. This method allows the precise arrangement of patient-derived colorectal tumors and healthy organoids, recapitulating the architecture of the primary tissue. It also enables the prediction of patients' response to chemotherapy and provides a quantitative indicator for better decision-making in treatment.
ADVANCED HEALTHCARE MATERIALS
(2022)
Article
Cell Biology
Tarini N. A. Gunawardena, Zoltan Bozoky, Claire Bartlett, Hong Ouyang, Paul D. W. Eckford, Theo J. Moraes, Felix Ratjen, Tanja Gonska, Christine E. Bear
Summary: In vitro studies on nasal epithelial cultures derived from cystic fibrosis patients suggest that the rescue effect of CFTR modulator drugs can be predicted through these studies. There is interest in evaluating different measuring methods for in vitro modulator responses in patient-derived nasal cultures. The fluorescence-based Fl-ACC method shows effectiveness in detecting positive responses to interventions for all genotypes and has the potential for greater sensitivity in detecting responses to pharmacological rescue strategies targeting W1282X.
Article
Multidisciplinary Sciences
Zhongyu Liu, Justin D. Anderson, Jennifer Natt, Jennifer S. Guimbellot
Summary: Individualized therapy for cystic fibrosis patients can be achieved through a well-differentiated organoid model that allows measurement of CFTR activity. The cultivation of HNE organoids requires the use of various imaging techniques for characterization and evaluation, enabling accurate differentiation between CF and non-CF organoids.
JOVE-JOURNAL OF VISUALIZED EXPERIMENTS
(2021)
Review
Biochemistry & Molecular Biology
Duncan E. Keegan, John J. Brewington
Summary: The emergence of highly effective CFTR modulator therapy has significantly improved healthcare for most cystic fibrosis (CF) patients. However, accessibility remains a challenge for some due to rare CFTR variants or lack of biologic activity of available therapies. The use of primary human cell-based models, particularly nasal cells, is proposed as a solution to address this gap and is crucial for personalized patient care in CF research.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Microbiology
Stephen Adonai Leon-Icaza, Salimata Bagayoko, Romain Verge, Nino Iakobachvili, Chloe Ferrand, Talip Aydogan, Celia Bernard, Angelique Sanchez Dafun, Marlene Murris-Espin, Julien Mazieres, Pierre Jean Bordignon, Serge Mazeres, Pascale Bernes-Lasserre, Victoria Rame, Jean-Michel Lagarde, Julien Marcoux, Marie-Pierre Bousquet, Christian Chalut, Christophe Guilhot, Hans Clevers, Peter J. Peters, Virginie Molle, Geanncarlo Lugo-Villarino, Kaymeuang Cam, Laurence Berry, Etienne Meunier, Celine Cougoule
Summary: Although Mabs infection can induce oxidative stress, pharmacological activation of antioxidant pathways can better control Mabs growth and reduce its virulence. Genetic and pharmacological inhibition of CFTR is associated with improved Mabs growth and increased virulence. Pharmacological activation of antioxidant pathways can inhibit Mabs growth and improve efficacy when combined with cefoxitin.
Article
Respiratory System
Eva Furstova, Tereza Dousova, Jakub Beranek, Malgorzata Libik, Libor Fila, Martin Modrak, Ondrej Cinek, Milan Macek, Pavel Drevinek
Summary: This study compared the in vitro responses of two CFTR modulator drug combinations and explored potential inter-individual variability in therapeutic response to the triple combination. The findings showed that elexacaftor/tezacaftor/ivacaftor was more effective than tezacaftor/ivacaftor in cystic fibrosis patients with a specific genotype. The presence of unique CFTR variants in one sample suggests that genetic traits beyond the CF-causing CFTR mutation may influence the response to modulator drugs.
JOURNAL OF CYSTIC FIBROSIS
(2022)
Review
Immunology
Samantha L. Tucker, Demba Sarr, Balazs Rada
Summary: Cystic Fibrosis is a genetic disease that causes chronic lung inflammation and infections, leading to high mortality rates. Immune system disruption in CF results in impaired immune responses, chronic infections with pathogens, and alterations in T cell and neutrophil functions. The role of P. aeruginosa and gMDSCs in T cell suppression and immune evasion in CF remains a subject of ongoing research.
FRONTIERS IN IMMUNOLOGY
(2021)
Article
Respiratory System
Sacha Spelier, Eyleen de Poel, Georgia N. Ithakisiou, Sylvia W. F. Suen, Marne C. Hagemeijer, Danya Muilwijk, Annelotte M. Vonk, Jesse E. Brunsveld, Evelien Kruisselbrink, Cornelis K. van der Ent, Jeffrey M. Beekman
Summary: This study developed a new screening format using intestinal organoids to test the CFTR-inducing potential of a FDA-approved drug library. The results showed that statins, specifically mevastatin, lovastatin, simvastatin, and fluvastatin, can increase CFTR function in organoids from patients with W1282X CFTR nonsense mutations. This study provides proof of principle for large-scale compound screening using patient-derived organoids.
Article
Cell & Tissue Engineering
Yun Weng, Simon Han, Maria T. Sekyi, Tao Su, Aras N. Mattis, Tammy T. Chang
Summary: Organoid self-assembly within rotating wall vessels (RWV) is a simple and high-throughput way to generate highly functional human-induced pluripotent stem cell-derived liver organoids without the need for Matrigel. Liver organoids self-assembled in RWVs demonstrate higher, broader, and more durable hepatic function than organoids generated on Matrigel, in part because Matrigel has some adverse effects on hepatic lineage commitment.
Article
Biochemistry & Molecular Biology
Tayyab Rehman, Philip H. Karp, Andrew L. Thurman, Steven E. Mather, Akansha Jain, Ashley L. Cooney, Patrick L. Sinn, Alejandro A. Pezzulo, Michael E. Duffey, Michael J. Welsh
Summary: This study found that inhibiting WNK kinases can increase the pH of airway surface liquid in cystic fibrosis and improve host defenses. WNK kinases regulate the secretion of HCO3- and the transport of Cl-, which affects the pH balance of airway fluid.
AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY
(2022)
Article
Oncology
Hannah G. McDonald, Megan M. Harper, Kristen Hill, Anqi Gao, Angelica L. Solomon, Charles J. Bailey, Miranda Lin, Mautin Barry-Hundeyin, Michael J. Cavnar, Samuel H. Mardini, Prakash J. Pandalai, Reema A. Patel, Jill M. Kolesar, Justin A. Rueckert, Lawrence Hookey, Mark Ropeleski, Shaila J. Merchant, Joseph Kim, Mei Gao
Summary: Gastric adenocarcinoma is a major cause of cancer-related deaths worldwide. We developed a novel methodology using patient-derived organoids (PDOs) to predict chemotherapy efficacy for these patients, which can help avoid unnecessary toxicities.
Review
Biochemistry & Molecular Biology
Irene Chamorro-Herrero, Alberto Zambrano
Summary: Respiratory diseases are a major cause of morbidity and mortality globally. Current treatments are mainly symptomatic, so there is a need for new strategies to understand these diseases and develop effective therapies. Stem cell and organoid technology has allowed the development of human pluripotent stem cell lines and differentiation protocols to create airways and lung organoids for disease modeling. Specifically, these organoids have been used to model respiratory diseases such as idiopathic pulmonary fibrosis, cystic fibrosis, chronic obstructive pulmonary disease, and COVID-19.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Pediatrics
Juliana Roda, Teresa Teixeira, Iris Ai Silva, Teresa Reis Silva, Ricardo Ferreira, Margarida D. Amaral, Guiomar Oliveira
Summary: This study characterized the clinical and genetic features of pediatric patients with CF in Portugal and identified candidates for CFTR modulator drugs. The results showed that the genetic and molecular characterization of CF is important for diagnosis, prognosis, and eligibility for treatment with CFTR modulator drugs.
JORNAL DE PEDIATRIA
(2022)
Article
Chemistry, Multidisciplinary
Donglong Fu, J. J. Erik Maris, Katarina Stanciakova, Nikolaos Nikolopoulos, Onno van Der Heijden, Laurens D. B. Mandemaker, Marijn E. Siemons, Desiree Salas Pastene, Lukas C. Kapitein, Freddy T. Rabouw, Florian Meirer, Bert M. Weckhuysen
Summary: This study utilizes advanced techniques to track the diffusion of single molecules in zeolite materials, revealing different motion behaviors of guest molecules in different zeolite channels, with the geometry of the zeolite channels determining diffusion anisotropy. Additionally, the study shows that the addition of secondary pore networks primarily enhances the diffusivity of sinusoidal zeolite channels, alleviating diffusion limitations of microporous zeolites.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2022)
Article
Biochemistry & Molecular Biology
Sofia S. Ramalho, Iris A. L. Silva, Margarida D. Amaral, Carlos M. Farinha
Summary: This study characterized the defects associated with four rare CFTR variants and assessed their response to approved corrector drugs. The results showed that these variants belonged to Class II mutations and had different responses to the corrector drugs, highlighting the need for personalized drug discovery initiatives.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Cell Biology
Ivar Noordstra, Cyntha M. van den Berg, Fransje W. J. Boot, Eugene A. Katrukha, Ka Lou Yu, Roderick P. Tas, Sybren Portegies, Bastiaan J. Viergever, Esther de Graaff, Casper C. Hoogenraad, Eelco J. P. de Koning, Francoise Carlotti, Lukas C. Kapitein, Anna Akhmanova
Summary: Insulin secretion in pancreatic beta-cells is regulated by cortical complexes that are enriched at the sites of adhesion to the extracellular matrix. Non-neuronal proteins LL5 beta and KANK1 are also present at insulin secretion sites and are involved in organizing exocytotic machinery. The dynamics of ELKS, an essential component of secretory complexes, is driven by binding and unbinding to low-mobility scaffolds, which are stimulated by glucose treatment. This study provides insights into the spatial organization of glucose-stimulated insulin release.
JOURNAL OF CELL SCIENCE
(2022)
Article
Cell Biology
Henk Karst, Femke S. den Boon, Niek Vervoort, Max Adrian, Lukas C. Kapitein, Marian Joels
Summary: The mineralocorticoid receptor (MR) in the mammalian brain mediates both genomic and non-genomic actions, possibly located near or translocated to the cell membrane. Although it is challenging to convincingly visualize membrane localization of endogenous MR or GFP-MR molecules, there is evidence suggesting that MR may be trafficked via beta-arrestin.
MOLECULAR AND CELLULAR ENDOCRINOLOGY
(2022)
Article
Cell Biology
Miqueias Lopes-Pacheco, Mafalda Bacalhau, Sofia S. Ramalho, Iris A. L. Silva, Filipa C. Ferreira, Graeme W. Carlile, David Y. Thomas, Carlos M. Farinha, John W. Hanrahan, Margarida D. Amaral
Summary: The study investigated the effects and mechanism of action of a newly developed F508del-CFTR corrector, MCG1516A, and found that it has additive effects to the FDA-approved corrector VX-661 in rescuing F508del-CFTR. Additionally, MCG1516A showed additive effects to genetic revertant R1070W, suggesting a potential binding site for this compound. This suggests that a combination of MCG1516A with other compounds could enhance correction of F508del-CFTR defects.
Article
Respiratory System
Margarida D. Amaral, Patrick T. Harrison
Summary: Despite advances in CF treatment, there is still a need to bring potentially curative therapies to all individuals with CF. This review discusses the missing aspects in treating all CF individuals and explores holistic approaches to identify drug targets and therapeutic approaches to correct the gene in its genome.
JOURNAL OF CYSTIC FIBROSIS
(2023)
Review
Neurosciences
Margarida D. Amaral
Summary: Biomedicine is challenged to treat diseases by understanding their dysfunctional processes. Cystic fibrosis, as a monogenic disorder, has been extensively studied through 'omic' approaches to identify novel drug targets.
JOURNAL OF PHYSIOLOGY-LONDON
(2023)
Article
Pharmacology & Pharmacy
Mafalda Bacalhau, Filipa C. Ferreira, Arthur Kmit, Felipe R. Souza, Veronica D. da Silva, Andre S. Pimentel, Margarida D. Amaral, Camilla D. Buarque, Miqueias Lopes-Pacheco
Summary: In this study, a collection of triazole compounds was screened to identify novel F508del-CFTR correctors. Four hit compounds, LSO-18, LSO-24, LSO-28, and LSO-39, were identified and shown to rescue F508del-CFTR processing, plasma membrane trafficking, and function. The mechanism of action of these compounds was investigated and it was found that LSO-18, LSO-24, and LSO-28 exhibited additive effects with the clinically approved drugs VX-661 and VX-445.
EUROPEAN JOURNAL OF PHARMACOLOGY
(2023)
Review
Pharmacology & Pharmacy
Luka A. Clarke, Margarida D. Amaral
Summary: RNA-based approaches for treating monogenic diseases include the use of small antisense oligonucleotides and mRNA administration. However, further optimization is needed for these methods.
Article
Health Care Sciences & Services
Mafalda Bacalhau, Filipa C. Ferreira, Iris A. L. Silva, Camilla D. Buarque, Margarida D. Amaral, Miqueias Lopes-Pacheco
Summary: The authors generated a new CFBE cell line to screen a collection of compounds and identified new potentiators for R334W-CFTR. The active compounds were validated by electrophysiological assays and showed enhanced chloride secretion. The combination of these compounds with VX-770 further enhanced CFTR function.
JOURNAL OF PERSONALIZED MEDICINE
(2023)
Review
Cell Biology
Malina K. Iwanski, Lukas C. Kapitein
Summary: Microtubules are essential for neuronal development and function, serving as tracks for intracellular transport and being involved in various neurodevelopmental and neurodegenerative disorders. The polar nature and composition of microtubules, including tubulin isotypes, post-translational modifications, associated proteins, stability, and orientation, play important roles in their function. Understanding these features and their effects on transport and organization in neurons is crucial.
FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY
(2023)
Article
Pediatrics
Henriette H. M. Dreyer, Eleonora Sofie van Tuyll van Serooskerken, Lisa W. Rodenburg, Arnold J. N. Bittermann, Hubertus G. M. Arets, Ellen M. B. P. Reuling, Johannes W. Verweij, Eric G. Haarman, David C. van der Zee, Stefaan H. A. J. Tytgat, Cornelis K. van der Ent, Jeffrey M. Beekman, Gimano D. Amatngalim, Maud Y. A. Lindeboom
Summary: Esophageal atresia (EA) is a rare birth defect with respiratory disorders as a major cause of morbidity. This study aimed to evaluate the feasibility of culturing and characterizing motile cilia function in airway epithelial cell cultures and 3D organoids derived from EA patients. The results showed that EA patient-derived airway epithelial cultures and organoids displayed normal motile cilia function, suggesting their potential use in studying the role of epithelial function in respiratory disorders in EA.
