FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W2900769069> ?p ?o ?g. }

• W2900769069 endingPage "1042" @default.
• W2900769069 startingPage "1040" @default.
• W2900769069 abstract "Kidney organoids, derived from human pluripotent stem cells, have the potential to greatly facilitate drug development. Boreström et al. have used CRISPR/Cas9 to create kidney fluorescent lineage markers for SIX2 and NPHS1 to monitor the differentiation process to tubular and glomerular structures and optimize maturity. The convergence of “personalized” kidney organoids with genome editing and single-cell sequencing technology hold great promise to result in better insight to disease, better human cell disease models, more predictive toxicology, and potentially “clinical trials in a dish.” Kidney organoids, derived from human pluripotent stem cells, have the potential to greatly facilitate drug development. Boreström et al. have used CRISPR/Cas9 to create kidney fluorescent lineage markers for SIX2 and NPHS1 to monitor the differentiation process to tubular and glomerular structures and optimize maturity. The convergence of “personalized” kidney organoids with genome editing and single-cell sequencing technology hold great promise to result in better insight to disease, better human cell disease models, more predictive toxicology, and potentially “clinical trials in a dish.” see basic research on page 1099 see basic research on page 1099 Twenty years ago, Thomson et al.1Thomson J.A. Itskovitz-Eldor J. Shapiro S.S. et al.Embryonic stem cell lines derived from human blastocysts.Science. 1998; 282: 1145-1147Crossref PubMed Scopus (12274) Google Scholar published the landmark paper reporting the successful stable culture of human embryonic stem cells. In 2007, Takahashi and Yamanaka2Takahashi K. Yamanaka S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors.Cell. 2006; 126: 663-676Abstract Full Text Full Text PDF PubMed Scopus (18861) Google Scholar reported a set of 4 defined factors that could revert somatic cells to pluripotent cells and labeled these cells “induced pluripotent stem cells” (iPSCs). In 2012, John Gurdon and Shinya Yamanaka won the Nobel Prize for their demonstration that adult somatic cells can be converted to the embryonic state. Over the subsequent 11 years since the introduction of iPSCs, there has been an explosion of human cell research applied to multiple organ systems, facilitated by the fact that iPSCs derived from adult somatic cells did not carry the ethical issues raised with the use of human blastocyst derived human embryonic stem cells. In the last 5 years, there have been significant developments in the refinement of protocols to generate 3-dimensional (3D) kidney organoids, derived from either human embryonic stem cells or iPSCs. The stem cells are treated with a series of small molecules and growth factors. Protocols take cues from what is known about normal human kidney development and result in 3D organoids consisting of kidney tissue that self-organizes into structures that have cellular and spatial characteristics of glomeruli, tubules, vasculature, and interstitium. This is a rapidly moving field of biology with potential for transformative impact on models of disease and drug development (Figure 1). The convergence of this technology with genome editing innovations, such as CRISPR-Cas 9 approaches, allows for introducing changes in the genome to not only track differentiation but also introduce genetic modifications that mimic human disease. Coupled with the powerful insight brought by single-cell sequencing technology, kidney organoids represent a powerful tool for conducting research using human models. The journal Nature Methods labeled organoids as the “method of the year 2017.”3Method of the year 2017: organoids.Nat Methods. 2018; 15: 1Crossref Scopus (36) Google Scholar It is heartening to see that advances made in kidney biology are contributing a great deal to the growing area of organoid technology. The applicability of human cell–derived kidney organoids are many. They can been used for better understanding of development, disease modeling, screening for new therapeutics, evaluation of therapeutic efficacy, and better understanding of human cellular response to nephrotoxicants and environmental factors. In this issue of Kidney International, Boreström et al.4Boreström C. Jonebring A. Guo J. et al.A CRISP(e)R view on kidney organoids allows generation of an induced pluripotent stem cell–derived kidney model for drug discovery.Kidney Int. 2018; 94: 1099-1110Abstract Full Text Full Text PDF PubMed Scopus (45) Google Scholar have used CRISPR/Cas9 to create kidney fluorescent lineage markers for SIX2 (marker of nephron progenitor cells) and NPHS1 (nephrin, marker for podocytes) to monitor the differentiation process to tubular and glomerular structures and facilitate kidney organoid generation to optimize maturity. They have introduced minor modifications to 2 other protocols to generate kidney organoids from human PSCs.5Takasato M. Er P.X. Chiu H.S. et al.Kidney organoids from human iPS cells contain multiple lineages and model human nephrogenesis.Nature. 2015; 526: 564-568Crossref PubMed Scopus (879) Google Scholar, 6Morizane R. Lam A.Q. Freedman B.S. et al.Nephron organoids derived from human pluripotent stem cells model kidney development and injury.Nat Biotechnol. 2015; 33: 1193-1200Crossref PubMed Scopus (509) Google Scholar They have extended the monolayer phase of differentiation of these prior protocols and made other modifications, concluding that these changes facilitated the generation of smaller organoids, which they argue will facilitate drug screening. Whereas others have also used reporter cell lines to guide the development of techniques to achieve directed differentiation of spatially restricted kidney structures7Morizane R. Bonventre J.V. Kidney organoids: a translational journey.Trends Mol Med. 2017; 23: 246-263Abstract Full Text Full Text PDF PubMed Scopus (85) Google Scholar and demonstrated that organoids can be generated in multiwell plates in configurations that will facilitate drug screening,7Morizane R. Bonventre J.V. Kidney organoids: a translational journey.Trends Mol Med. 2017; 23: 246-263Abstract Full Text Full Text PDF PubMed Scopus (85) Google Scholar, 8Czerniecki S.M. Cruz N.M. Harder J.L. et al.High-throughput screening enhances kidney organoid differentiation from human pluripotent stem cells and enables automated multidimensional phenotyping.Cell Stem Cell. 2018; 22: 929-940Abstract Full Text Full Text PDF PubMed Scopus (238) Google Scholar the field is rapidly evolving and new protocols both validate aspects of prior approaches and suggest additional modifications. The world-wide prevalence of kidney disease is rapidly growing, and the therapeutic repertoire for these patients is very limited. It is of great interest to use human cell models to discover new drugs, as it is hoped that these human 3D kidney models will predict efficacy and toxicity in humans to a greater extent than predicted by 2D culture models or animal models. Two-dimensional cultured immortalized cell models suffer from changes in metabolism and dedifferentiation, losing tissue-related functions that limit their applicability to translation, whereas 3D organoid models allow for bidirectional communication among various more differentiated cell types in the surrounding environment. Although animal models have contributed a great deal to drug development and will continue to do so, some of the models of disease in animals do not mimic the disease process in man and animal tissue may not respond in ways that are similar to human tissue. Boreström et al.4Boreström C. Jonebring A. Guo J. et al.A CRISP(e)R view on kidney organoids allows generation of an induced pluripotent stem cell–derived kidney model for drug discovery.Kidney Int. 2018; 94: 1099-1110Abstract Full Text Full Text PDF PubMed Scopus (45) Google Scholar conclude that the organoids they generate have transcriptomic profiles that resemble those of adult kidney. They have carried out single-cell RNA sequencing technology and have found the podocyte-enriched cluster and tubular clusters were clustered closely with glomerular and tubulointerstitial renal compartments, respectively, based on a set of known markers previously reported from microarray data from the human kidney. While it is certainly desirable to obtain organoids with more differentiated structures, there are some questions about the product of the differentiation protocol developed by the group. The persistence of SIX2 expression through day 20 of differentiation suggests a growing subpopulation of nephron progenitor cells that persists in parallel with more differentiated structures. Thus only a fraction of the kidney structures are differentiated. Clearly the more differentiated the organoid, the more it is likely to behave like human tissue and predict pathogenesis, toxicity, and drug efficacy in man. It is somewhat surprising that the clusters created from RNA-sequencing (RNA-Seq) data contain only podocytes, proximal tubule cells, and progenitor populations. Other published protocols have identified more complex collections of cells in organoids, with characteristics of proximal tubules, distal tubules, ascending limb, and collecting ducts, as well as podocytes and endothelial cells. Wu et al.9Wu H, Uchimura K, Donnelly E, et al. Comparative analysis of kidney organoid and adult human kidney single cell and single nucleus transcriptomes. bioRxiv. 10.1101/232561. Accessed October 21, 2018.Google Scholar have evaluated single-cell gene expression in large numbers of cells isolated from kidney organoids that were derived from stem cells using the 2 protocols5Takasato M. Er P.X. Chiu H.S. et al.Kidney organoids from human iPS cells contain multiple lineages and model human nephrogenesis.Nature. 2015; 526: 564-568Crossref PubMed Scopus (879) Google Scholar, 6Morizane R. Lam A.Q. Freedman B.S. et al.Nephron organoids derived from human pluripotent stem cells model kidney development and injury.Nat Biotechnol. 2015; 33: 1193-1200Crossref PubMed Scopus (509) Google Scholar cited as starting points for the Boreström protocol. Wu et al. found that a diverse range of kidney cells as well as endothelial and neuronal cells characterized the organoids. It is not clear why more cell types were not identified in the analysis of Boreström et al.4Boreström C. Jonebring A. Guo J. et al.A CRISP(e)R view on kidney organoids allows generation of an induced pluripotent stem cell–derived kidney model for drug discovery.Kidney Int. 2018; 94: 1099-1110Abstract Full Text Full Text PDF PubMed Scopus (45) Google Scholar That there are limited clusters may relate to the small number of cells that were analyzed by single-cell RNA sequencing (scRNA-Seq). For example, endothelial cells were identified by immunocytochemistry but not detected by scRNA-Seq. It is also surprising that the single-cell analysis did not identify any significant stromal compartment usually present in organoids. To further evaluate whether the organoids are more mature than those previously reported, it will be necessary to increase the number of cells evaluated by scRNA-Seq and perform more direct comparisons “head-to-head” with scRNA-Seq analyses of human normal kidney tissue.9Wu H, Uchimura K, Donnelly E, et al. Comparative analysis of kidney organoid and adult human kidney single cell and single nucleus transcriptomes. bioRxiv. 10.1101/232561. Accessed October 21, 2018.Google Scholar There has been a good deal of discussion regarding the state of maturity of the organoids with many arguing that they may represent first or perhaps second trimester equivalents. Organoids have been shown to express markers of differentiation characteristic of the adult kidney. It is also important to recognize that the goal is to find new disease models and predictive models for drug discovery, including efficacy and toxicity as well as other applications. Models should be “fit for purpose” and have already been proven useful for mimicking developmental and disease processes despite potential limitations on differentiation status. Full maturity may not be necessary for a particular therapeutic discovery or analytical approach. There have already been demonstrations of kidney models of polycystic kidney disease and organoids of other tissues have served as useful testing models bringing new insight into disease processes and motivating pursuit of therapeutic directions. Although there have been very encouraging initial studies that demonstrate the promise of organoids, much is left to do to enhance approaches that will optimize these “mini-kidneys” so that they will live up to their potential to transform our approach to drug discovery. Like any model of human disease they will have limitations. One of the important limitations is the absence of a developed vasculature. While progress is being made to increase endothelial cell and vascular structures in vitro, placement of kidney organoids into the rodent has been demonstrated to result in vascular infiltration from the host. Advances in tissue engineering are likely to lead to in vitro systems to incorporate vascular perfusion. Another limitation is variability among organoids. This variability affects comparisons of organoids derived from different patients because often different iPSCs have slightly different optimal conditions for kidney organoid generation. Even if the organoids are generated from the same iPSC line, there may also be heterogeneity. This limitation, like others, will evolve to be less problematic as fine-tuning of conditions of organoid generation will continue to evolve. The generation of larger organoids will depend on providing systems for adequate oxygenation, nutrient supply, and waste metabolite removal. These issues are also amenable to innovative bioengineering approaches. Another challenge related to the use of organoids is the current limitations in measurement of functionality. This will likely be approached by the application of the ever more sophisticated and miniaturized development of nano- and microsensors as well as the development of engineered systems that can allow for functional measurements. Another current limitation of kidney organoids is the absence of inflammatory cells. Many disease processes involve interaction of tubules and/or glomeruli with infiltrating cells. It is likely that systems will be developed that incorporate inflammatory cells and because of the ability to control the cellular environment ex vivo the organoid system may provide a better way to dissect out interactions among particular cell types. In conclusion, kidney organoids represent a new important weapon in the fight against kidney disease. We now have 3D systems that we can use for a personalized approach to better understand abnormalities of development and pathobiology of genetic and nongenetic diseases of the kidney using human tissue. We can use the organoids to not only model disease but to screen for new therapeutics or test potential therapeutic agents. We can also use them as sensitive indicators of nephrotoxicity. Despite limitations intrinsic to any new model system, these structures hold great promise to advance therapeutic discovery in kidney diseases. JVB is cofounder and owns equity in Goldfinch Bio. He also is co-inventor on patents related to organoid protocols that have been assigned to Partners Healthcare. A CRISP(e)R view on kidney organoids allows generation of an induced pluripotent stem cell–derived kidney model for drug discoveryKidney InternationalVol. 94Issue 6PreviewDevelopment of physiologically relevant cellular models with strong translatability to human pathophysiology is critical for identification and validation of novel therapeutic targets. Herein we describe a detailed protocol for generation of an advanced 3-dimensional kidney cellular model using induced pluripotent stem cells, where differentiation and maturation of kidney progenitors and podocytes can be monitored in live cells due to CRISPR/Cas9-mediated fluorescent tagging of kidney lineage markers (SIX2 and NPHS1). Full-Text PDF Open Access" @default.
• W2900769069 created "2018-11-29" @default.
• W2900769069 creator A5089781525 @default.
• W2900769069 date "2018-12-01" @default.
• W2900769069 modified "2023-10-10" @default.
• W2900769069 title "Kidney organoids—a new tool for kidney therapeutic development" @default.
• W2900769069 cites W1802574002 @default.
• W2900769069 cites W2086943348 @default.
• W2900769069 cites W2125987139 @default.
• W2900769069 cites W2192723508 @default.
• W2900769069 cites W2587426589 @default.
• W2900769069 cites W2783751875 @default.
• W2900769069 cites W2803499747 @default.
• W2900769069 cites W2887161891 @default.
• W2900769069 cites W4231410563 @default.
• W2900769069 doi "https://doi.org/10.1016/j.kint.2018.07.029" @default.
• W2900769069 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/30466559" @default.
• W2900769069 hasPublicationYear "2018" @default.
• W2900769069 type Work @default.
• W2900769069 sameAs 2900769069 @default.
• W2900769069 citedByCount "14" @default.
• W2900769069 countsByYear W29007690692020 @default.
• W2900769069 countsByYear W29007690692021 @default.
• W2900769069 countsByYear W29007690692022 @default.
• W2900769069 countsByYear W29007690692023 @default.
• W2900769069 crossrefType "journal-article" @default.
• W2900769069 hasAuthorship W2900769069A5089781525 @default.
• W2900769069 hasBestOaLocation W29007690691 @default.
• W2900769069 hasConcept C104317684 @default.
• W2900769069 hasConcept C126322002 @default.
• W2900769069 hasConcept C145103041 @default.
• W2900769069 hasConcept C2777632694 @default.
• W2900769069 hasConcept C2780091579 @default.
• W2900769069 hasConcept C31695470 @default.
• W2900769069 hasConcept C54355233 @default.
• W2900769069 hasConcept C70721500 @default.
• W2900769069 hasConcept C71924100 @default.
• W2900769069 hasConcept C86803240 @default.
• W2900769069 hasConcept C95444343 @default.
• W2900769069 hasConceptScore W2900769069C104317684 @default.
• W2900769069 hasConceptScore W2900769069C126322002 @default.
• W2900769069 hasConceptScore W2900769069C145103041 @default.
• W2900769069 hasConceptScore W2900769069C2777632694 @default.
• W2900769069 hasConceptScore W2900769069C2780091579 @default.
• W2900769069 hasConceptScore W2900769069C31695470 @default.
• W2900769069 hasConceptScore W2900769069C54355233 @default.
• W2900769069 hasConceptScore W2900769069C70721500 @default.
• W2900769069 hasConceptScore W2900769069C71924100 @default.
• W2900769069 hasConceptScore W2900769069C86803240 @default.
• W2900769069 hasConceptScore W2900769069C95444343 @default.
• W2900769069 hasIssue "6" @default.
• W2900769069 hasLocation W29007690691 @default.
• W2900769069 hasLocation W29007690692 @default.
• W2900769069 hasOpenAccess W2900769069 @default.
• W2900769069 hasPrimaryLocation W29007690691 @default.
• W2900769069 hasRelatedWork W1489599660 @default.
• W2900769069 hasRelatedWork W1857667560 @default.
• W2900769069 hasRelatedWork W2012010213 @default.
• W2900769069 hasRelatedWork W2018701070 @default.
• W2900769069 hasRelatedWork W2362741529 @default.
• W2900769069 hasRelatedWork W2414977084 @default.
• W2900769069 hasRelatedWork W2766746427 @default.
• W2900769069 hasRelatedWork W2907303210 @default.
• W2900769069 hasRelatedWork W2992164897 @default.
• W2900769069 hasRelatedWork W4214527210 @default.
• W2900769069 hasVolume "94" @default.
• W2900769069 isParatext "false" @default.
• W2900769069 isRetracted "false" @default.
• W2900769069 magId "2900769069" @default.
• W2900769069 workType "article" @default.