Organoids are not organs: Sources of variation and misinformation in organoid biology

Stem Cell Reports, Год журнала: 2023, Номер 18(6), С. 1255 - 1270

Опубликована: Июнь 1, 2023

In the past decade, term organoid has moved from obscurity to common use describe a 3D in vitro cellular model of tissue that recapitulates structural and functional elements vivo organ it models. The is now applied structures formed as result two distinct processes: capacity for adult epithelial stem cells re-create niche ability direct differentiation pluripotent self-organizing multicellular organogenesis. While these fields rely upon different cell types recapitulate processes, both share challenges around robustness, accuracy, reproducibility. Critically, organoids are not organs. This commentary serves discuss challenges, how they impact genuine utility, shine light on need improve standards all approaches.

Язык: Английский

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3D Hydrogel Encapsulation Regulates Nephrogenesis in Kidney Organoids

Advanced Materials, Год журнала: 2024, Номер 36(14)

Опубликована: Янв. 5, 2024

Stem cell-derived kidney organoids contain nephron segments that recapitulate morphological and functional aspects of the human kidney. However, directed differentiation protocols for are largely conducted using biochemical signals to control differentiation. Here, hypothesis mechanical regulate nephrogenesis is investigated in 3D culture by encapsulating within viscoelastic alginate hydrogels with varying rates stress relaxation. Tubular significantly more convoluted differentiated when compared those suspension culture. Hydrogel viscoelasticity regulates spatial distribution differentiating organoids. Consistent these observations, a particle-based computational model predicts extent deformation hydrogel-organoid interface morphology segments. Elevated extracellular calcium levels medium, which can be impacted hydrogels, decrease glomerulus-to-tubule ratio These findings reveal hydrogel encapsulation patterning suggest microenvironment an important design variable regenerative medicine.

Язык: Английский

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Human organoids-on-chips for biomedical research and applications

Theranostics, Год журнала: 2024, Номер 14(2), С. 788 - 818

Опубликована: Янв. 1, 2024

Human organoids-on-chips (OrgOCs) are the synergism of human organoids (HOs) technology and microfluidic organs-on-chips (OOCs).OOCs can mimic extrinsic characteristics organs, such as environmental clues living tissue, while HOs more amenable to biological analysis genetic manipulation.By spatial cooperation, OrgOCs served 3D organotypic models allowing them recapitulate critical tissue-specific properties forecast responses outcomes.It represents a giant leap forward from regular 2D cell monolayers animal in improved ecological niche modeling.In recent years, have offered potential promises for clinical studies advanced preclinical-to-clinical translation medical industrial fields.In this review, we highlight cutting-edge achievements OrgOCs, introduce key features architectures, share revolutionary applications basic biology, disease modeling, preclinical assay precision medicine.Furthermore, discuss how combine wide range disciplines with accelerate translational applications, well challenges opportunities biomedical research applications.

Язык: Английский

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Enhanced metanephric specification to functional proximal tubule enables toxicity screening and infectious disease modelling in kidney organoids

Nature Communications, Год журнала: 2022, Номер 13(1)

Опубликована: Окт. 8, 2022

While pluripotent stem cell-derived kidney organoids are now being used to model renal disease, the proximal nephron remains immature with limited evidence for key functional solute channels. This may reflect early mispatterning of nephrogenic mesenchyme and/or insufficient maturation. Here we show that enhanced specification metanephric progenitors results in elongated and radially aligned proximalised nephrons distinct S1 - S3 tubule cell types. Such PT-enhanced possess improved albumin organic cation uptake, appropriate KIM-1 upregulation response cisplatin, expression SARS-CoV-2 entry factors resulting increased viral replication. The striking proximo-distal orientation resulted from localized WNT antagonism originating organoid stromal core. represent an study inherited acquired tubular disease as well drug responses.

Язык: Английский

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A single-cell multiomic analysis of kidney organoid differentiation

Proceedings of the National Academy of Sciences, Год журнала: 2023, Номер 120(20)

Опубликована: Май 8, 2023

Kidney organoids differentiated from pluripotent stem cells are powerful models of kidney development and disease but characterized by cell immaturity off-target fates. Comparing the cell-specific gene regulatory landscape during organoid differentiation with human adult can serve to benchmark progress in at epigenome transcriptome level for individual types. Using single-cell multiome histone modification analysis, we report more broadly open chromatin types compared kidney. We infer enhancer dynamics cis-coaccessibility analysis validate an driving transcription HNF1B CRISPR interference both cultured proximal tubule also differentiation. Our approach provides experimental framework judge maturation state shows that be used networks regulate

Язык: Английский

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Selective induction of human renal interstitial progenitor-like cell lineages from iPSCs reveals development of mesangial and EPO-producing cells

Cell Reports, Год журнала: 2024, Номер 43(2), С. 113602 - 113602

Опубликована: Янв. 17, 2024

Recent regenerative studies using human pluripotent stem cells (hPSCs) have developed multiple kidney-lineage and organoids. However, to further form functional segments of the kidney, interactions epithelial interstitial are required. Here we describe a selective differentiation renal progenitor-like (IPLCs) from induced (hiPSCs) by modifying our previous induction method for nephron progenitor (NPCs) analyzing mouse embryonic cell (IPC) development. Our IPLCs combined with hiPSC-derived NPCs nephric duct nephrogenic niche- mesangium-like structures in vitro. Furthermore, successfully induce differentiate into mesangial erythropoietin-producing lineages vitro screening differentiation-inducing factors confirm that p38 MAPK, hypoxia, VEGF signaling pathways involved mesangial-lineage cells. These findings indicate IPC-lineage contributes kidney regeneration developmental research.

Язык: Английский

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Advancing preclinical drug evaluation through automated 3D imaging for high-throughput screening with kidney organoids

Biofabrication, Год журнала: 2024, Номер 16(3), С. 035003 - 035003

Опубликована: Март 28, 2024

High-throughput drug screening is crucial for advancing healthcare through discovery. However, a significant limitation arises from availablein vitromodels using conventional 2D cell culture, which lack the proper phenotypes and architectures observed in three-dimensional (3D) tissues. Recent advancements stem biology have facilitated generation of organoids-3D tissue constructs that mimic human organsin vitro. Kidney organoids, derived pluripotent cells, represent breakthrough disease representation. They encompass major kidney types organized within distinct nephron segments, surrounded by stroma endothelial cells. This allows assessment structural alterations such as loss, characteristic chronic disease. Despite these advantages, complexity 3D structures has hindered use organoids large-scale screening, pipelines utilizing complexin remain to be established high-throughput screening. In this study, we address technical limitations fully automated imaging, aided machine-learning approach automatic profiling segment-specific epithelial morphometry. were exposed nephrotoxic agent cisplatin model severe acute injury. An U.S. Food Drug Administration (FDA)-approved library was tested therapeutic nephrotoxicity The pipeline image acquisition analysis identified or drugs during chemotherapy. potential aligned with previousin vivoand reports. Additionally, Imatinib, tyrosine kinase inhibitor used hematological malignancies, preventive therapy cisplatin-induced Our proof-of-concept report demonstrates process, morphometric assays enables constructs.

Язык: Английский

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Long-term expandable mouse and human-induced nephron progenitor cells enable kidney organoid maturation and modeling of plasticity and disease

Cell stem cell, Год журнала: 2024, Номер 31(6), С. 921 - 939.e17

Опубликована: Апрель 30, 2024

Язык: Английский

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Patterning the nephron: Forming an axial polarity with distal and proximal specialization

Current topics in developmental biology/Current Topics in Developmental Biology, Год журнала: 2025, Номер unknown

Опубликована: Янв. 1, 2025

Язык: Английский

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Human and rat renal proximal tubule in vitro models for ADME applications

Archives of Toxicology, Год журнала: 2025, Номер unknown

Опубликована: Март 4, 2025

Abstract The kidney is a major organ dictating excretion rates of chemicals and their metabolites from the body thus renal clearance frequently component pharmaco-(toxico)-kinetic profiles. Within nephron, proximal tubule site for xenobiotic reabsorption glomerular filtrate secretion blood into lumen via expression multiple inward (lumen to interstitium) outward transport systems (interstitium lumen). While there exist several human tubular cell culture options that could be utilized modelling clearance, they do not necessarily represent full complement processes in vivo counterparts. Here, we review available rat vitro models, including subcellular fractions, immortalized lines, primary cultures, induced pluripotent stem (iPSC)-derived models also consider more organotypic environments such as microporous growth supports, organoids microfluidic systems. This focuses on levels function transporters phase I II metabolizing enzymes these order critically assess usefulness identify potential solutions overcome identified limitations.

Язык: Английский

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