Intestinal organoids to model cystic fibrosis

Mourik, Peter van; Beekman, Jeffrey M.; Ent, Cornelis K. van der

doi:10.1183/13993003.02379-2018

Cited by 35 publications

(23 citation statements)

References 39 publications

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“…In addition, the possibility of expanding iPSC-derived HIOs to an unlimited number, thanks to the maintenance of an intestinal stem-cell subpopulation, makes it very attractive for high-throughput screening in 384-well plates when combined with automated live microscopy. Indeed, pharmaceutical companies have already started to integrate intestinal organoids in their drugdiscovery pipeline 28 . It is important to keep in mind, however, that until exhaustive comparisons are performed, it cannot formally be ruled out that drug responses of certain CFTR variants can vary in a tissue-specific manner due to the recruitment of different cis-regulatory elements nearby or within the CFTR locus.…”

Section: Discussionmentioning

confidence: 99%

“…The functionality of the FIS assay has been demonstrated in primary HIO obtained by crypt isolation during rectal biopsies 28 , but not in iPSC-derived organoids. We, therefore, introduced several modifications to the maturation step of the original differentiation protocol in order to generate iPSC-derived HIOs that more closely resembled biopsy HIOs (Figure 3C; manuscript in preparation).…”

Section: Directed Differentiation Of the Cftr Mutant And Corrected Ipscs Toward Cftr-expressing Intestinal Organoidsmentioning

confidence: 99%

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iPSC-Derived Intestinal Organoids from Cystic Fibrosis Patients Acquire CFTR Activity upon TALEN-Mediated Repair of the p.F508del Mutation

Fleischer¹,

Vallejo-Díez

Martín-Fernández³

et al. 2020

Molecular Therapy - Methods & Clinical Development

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Cystic fibrosis (CF) is the main genetic cause of death among the Caucasian population. The disease is characterized by abnormal fluid and electrolyte mobility across secretory epithelia. The first manifestations occur within hours of birth (meconium ileus), later extending to other organs, generally affecting the respiratory tract. It is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. CFTR encodes a cyclic adenosine monophosphate (cAMP)-dependent, phosphorylation-regulated chloride channel required for transport of chloride and other ions through cell membranes. There are more than 2,000 mutations described in the CFTR gene, but one of them, phenylalanine residue at amino acid position 508 (p.F508del), a recessive allele, is responsible for the vast majority of CF cases worldwide. Here, we present the results of the application of genome-editing techniques to the restoration of CFTR activity in p.F508del patient-derived induced pluripotent stem cells (iPSCs). Gene-edited iPSCs were subsequently used to produce intestinal organoids on which the physiological activity of the restored gene was tested in forskolin-induced swelling tests. The seamless restoration of the p.F508del mutation resulted in normal expression of the mature CFTR glycoprotein, full recovery of CFTR activity, and a normal response of the repaired organoids to treatment with two approved CF therapies: VX-770 and VX-809.

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Section: Discussionmentioning

confidence: 99%

Section: Directed Differentiation Of the Cftr Mutant And Corrected Ipscs Toward Cftr-expressing Intestinal Organoidsmentioning

confidence: 99%

iPSC-Derived Intestinal Organoids from Cystic Fibrosis Patients Acquire CFTR Activity upon TALEN-Mediated Repair of the p.F508del Mutation

Fleischer¹,

Vallejo-Díez

Martín-Fernández³

et al. 2020

Molecular Therapy - Methods & Clinical Development

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“…A successful new feature in the journal is "ERJ methods" which was introduced in 2018 to give a guide to readers on the diverse and sometimes complex methodologies used in our speciality [42][43][44][45][46][47][48][49]. These are short mini-review papers intended to give non-experts the information required to understand and interpret the basics of cutting-edge methods.…”

Section: Erj Methods Are Taking Offmentioning

confidence: 99%

The evolution of the European Respiratory Journal: ready for the new decade!

Chalmers

Reeves²,

Bullen³

et al. 2020

Eur Respir J

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The year started with publication of the proceedings of the 6 th World Symposium on Pulmonary Hypertension, providing key updates on pathogenesis, genetics, diagnosis and treatment of all classes of pulmonary hypertension [1-14]. The World Symposium has been held every 5 years since 1973 and the proceedings provide comprehensive guidance on the state of the art in pulmonary vascular disease. This series was published in the ERJ for the first time in its 45-year history, and perhaps the most impactful article of the series was that on the new haemodynamic definitions and updated clinical classification of pulmonary hypertension [5]. This document proposed a threshold of pulmonary artery pressure >20 mmHg to define clinically significant disease. Whether or not this new threshold should lead to a rewriting of the textbooks of medicine was addressed in a pro/con editorial a few months later, and generated significant debate [15-20]. The series further discussed future clinical trial design and also the critical impact of patient perspectives [9, 14]. The entire series was published open access in acknowledgement of the critical nature of these articles for the global pulmonary community. The ERJ has two regular review series: "state of the art", which aims to give a high impact current update on key clinical and translational topics; and "back to basics", which provides accessible reviews of basic and translational science topics [21, 22]. 2019 saw a focus on COPD, with reviews and perspectives focused on controversial topics, including the role of inhaled corticosteroids, early COPD, and imaging and biomarkers [23-25]. Precision medicine in COPD and airways disease continues to develop and will have more and more impact on clinical respirology in the near future [26-28]. One major aspect is the question about how to assess airway inflammation in practice. The Global Initiative for Chronic Obstructive Lung Disease (GOLD) science committee published the justification for the recent GOLD strategy update in 2019, explaining the decision to include blood eosinophils in the decision-making process for use of inhaled corticosteroids for the first time [29]. Treatable traits, a concept originally

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“…The use of human intestinal organoids grown from crypt fragments was characterized for the study of cystic fibrosis (CF), caused by mutations in the cystic fibrosis transmembrane conductance regulator gene (CFTR) that encodes epithelial anion channels (Dekkers et al 2016). Organoids have been used in preclinical studies to identify and develop CFTR modulating drugs and to study the mechanisms associated with differences in CFTR functioning (Van Mourik et al 2019). In a study on organoids by Dekkers et al, CFTR mutations and additional patient specific genetic traits were shown to modify the response to CFTR modulators (Dekkers et al 2016).…”

Section: Use Of Organoids As Test Systems For Drugs Screeningmentioning

confidence: 99%

3D organotypic cell structures for drug development and Microorganism-Host interaction research

Zubareva¹,

Nadezhdin²,

Nadezhdina³

et al. 2021

RRP

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Introduction: The article describes a new method of tissue engineering, which is based on the use of three-dimensional multicellular constructs consisting of stem cells that mimic the native tissue in vivo – organoids. 3D cell cultures: The currently existing model systems of three-dimensional cultures are described. Characteristics of organoids and strategies for their culturing: The main approaches to the fabrication of 3D cell constructs using pluripotent (embryonic and induced) stem cells or adult stem cells are described. Brain organoids (Cerebral organoids): Organoids of the brain, which are used to study the development of the human brain, are characterized, with the description of biology of generating region-specific cerebral organoids. Lung organoids: Approaches to the generation of lung organoids are described, by means of pluripotent stem cells and lung tissue cell lines. Liver organoids: The features of differentiation of stem cells into hepatocyte-like cells and the creation of 3D hepatic organoids are characterized. Intestinal organoids: The formation of small intestine organoids from stem cells is described. Osteochondral organoids: Fabrication of osteochondral organoids is characterised. Use of organoids as test systems for drugs screening: The information on drug screening using organoids is provided. Using organoids to model infectious diseases and study adaptive responses of microorganisms when interacting with the host: The use of organoids for modeling infectious diseases and studying the adaptive responses of microorganisms when interacting with the host organism is described. Conclusion: The creation of three-dimensional cell structures that reproduce the structural and functional characteristics of tissue in vivo, makes it possible to study the biology of the body’s development, the features of intercellular interactions, screening drugs and co-cultivating with viruses, bacteria and parasites.

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Intestinal organoids to model cystic fibrosis

Abstract: ERSpublicationsCF can be studied using patient-specific intestinal organoids. CFTR protein function in intestinal organoids correlates with clinical disease severity and drug testing in organoids could aid in finding drugs for people with rare CFTR mutations.

Cited by 35 publications

References 39 publications

iPSC-Derived Intestinal Organoids from Cystic Fibrosis Patients Acquire CFTR Activity upon TALEN-Mediated Repair of the p.F508del Mutation

iPSC-Derived Intestinal Organoids from Cystic Fibrosis Patients Acquire CFTR Activity upon TALEN-Mediated Repair of the p.F508del Mutation

The evolution of the European Respiratory Journal: ready for the new decade!

3D organotypic cell structures for drug development and Microorganism-Host interaction research

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