ORCID Profile
0000-0002-3077-5582
Current Organisations
Utrecht University
,
Princess Máxima center for pediatric oncology
,
Hubrecht Institute
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Publisher: Springer Science and Business Media LLC
Date: 02-08-2023
DOI: 10.1038/S41467-023-40298-7
Abstract: Plasmodium falciparum ( Pf ) parasite development in liver represents the initial step of the life-cycle in the human host after a Pf- infected mosquito bite. While an attractive stage for life-cycle interruption, understanding of parasite-hepatocyte interaction is inadequate due to limitations of existing in vitro models. We explore the suitability of hepatocyte organoids (HepOrgs) for Pf -development and show that these cells permitted parasite invasion, differentiation and maturation of different Pf strains. Single-cell messenger RNA sequencing (scRNAseq) of Pf- infected HepOrg cells has identified 80 Pf- transcripts upregulated on day 5 post-infection. Transcriptional profile changes are found involving distinct metabolic pathways in hepatocytes with Scavenger Receptor B1 (SR-B1) transcripts highly upregulated. A novel functional involvement in schizont maturation is confirmed in fresh primary hepatocytes. Thus, HepOrgs provide a strong foundation for a versatile in vitro model for Pf liver-stages accommodating basic biological studies and accelerated clinical development of novel tools for malaria control.
Publisher: The Company of Biologists
Date: 2017
DOI: 10.1242/DMM.029876
Abstract: The gastric epithelium consists of tubular glandular units each containing several differentiated cells types, and populations of stem cells, which enable the stomach to secrete the acid, mucus and various digestive enzymes required for its function. Cell signalling provides cues to regulate development and homeostasis of adult tissues, however very little is known about which cell signalling pathways are required for homeostasis of the gastric epithelium. Many diseases, such as cancer, arise as a result of deregulation to signalling pathways that regulate homeostasis of the diseased organ. Therefore it is important to understand the biology of how normal conditions are maintained in a tissue to help inform the mechanisms driving disease in that same tissue, and identify potential points of therapeutic intervention. Wnt signalling regulates several cell functions including proliferation, differentiation and migration, and plays a critical role during homeostasis of several tissues, including the intestinal epithelium. Wnt3a is required in the culture medium of gastric organoids, suggesting it is also important for the homeostasis of the gastric epithelium, but this has not been investigated in vivo. Here we show that the Wnt receptor Frizzled7 (Fzd7), which is required for the homeostasis of the intestine, is expressed in the gastric epithelium and is required for gastric organoid growth. Gastric specific loss of Fzd7 in the adult gastric epithelium of mice is deleterious and triggers rapid epithelial repopulation, which we believe is the first observation of this novel function for this tissue. Taken together these data provide functional evidence of a critical role for Wnt signalling, via the Fzd7 receptor, during homeostasis of the gastric epithelium.
Publisher: Springer Science and Business Media LLC
Date: 11-03-2020
DOI: 10.1038/S41467-020-15155-6
Abstract: Kidney tumours are among the most common solid tumours in children, comprising distinct subtypes differing in many aspects, including cell-of-origin, genetics, and pathology. Pre-clinical cell models capturing the disease heterogeneity are currently lacking. Here, we describe the first paediatric cancer organoid biobank. It contains tumour and matching normal kidney organoids from over 50 children with different subtypes of kidney cancer, including Wilms tumours, malignant rhabdoid tumours, renal cell carcinomas, and congenital mesoblastic nephromas. Paediatric kidney tumour organoids retain key properties of native tumours, useful for revealing patient-specific drug sensitivities. Using single cell RNA-sequencing and high resolution 3D imaging, we further demonstrate that organoid cultures derived from Wilms tumours consist of multiple different cell types, including epithelial, stromal and blastemal-like cells. Our organoid biobank captures the heterogeneity of paediatric kidney tumours, providing a representative collection of well-characterised models for basic cancer research, drug-screening and personalised medicine.
Publisher: Proceedings of the National Academy of Sciences
Date: 23-07-2021
Abstract: In the mammalian ovary, primordial germ cells maintain a genomic program associated with pluripotency until they stop proliferating, move toward oogenesis, and enter meiosis. The molecular mechanisms that enable primordial germ cells to exit pluripotency and enter meiosis in a timely manner are unclear, and their identification represents a major challenge in reproductive biology because the fertility of each in idual depends on this. Evidence that cessation of germ cell proliferation is a cell-autonomous event, unrelated to the number of cell isions, led to a search for an intrinsic timing mechanism that has long remained elusive. We describe here that WNT/β-catenin signaling regulates this timing and coordinates the transition from pluripotent to gametogenesis-competent germ cells.
Publisher: Cold Spring Harbor Laboratory
Date: 29-10-2020
DOI: 10.1101/2020.10.29.358622
Abstract: Uropathogenic Escherichia coli (UPEC) is the most common cause of urinary tract infections (UTIs) requiring antibiotic therapy. Recurrent infections, which occur in a quarter of treated in iduals, may arise from “quiescent intracellular reservoirs” of bacteria that invade deeper layers of the bladder wall following infection and exfoliation of superficial umbrella cells. Here, we present a novel bladder organoid model of UPEC infection that recapitulates the stratified bladder architecture within a small volume suitable for live-cell imaging of host-pathogen dynamics with high spatiotemporal resolution. We confirm that bacteria injected into the organoid lumen rapidly enter superficial cells that resemble umbrella cells and proliferate to generate tightly packed colonies that resemble intracellular bacterial communities (IBCs), a hallmark of UPEC pathogenesis. Unexpectedly, at early stages of infection we detect in idual “solitary” bacteria that penetrate deeper layers of the organoid wall, where they evade killing by antibiotics and neutrophils. Volumetric serial block face scanning electron microscopy of infected organoids reveals that solitary bacteria can be found throughout the bladder wall and may be intracellular or pericellular (sandwiched between uroepithelial cells). Unlike bacteria within IBCs, which are coccoid-shaped and non-flagellated, solitary bacteria within the bladder wall are rod-shaped and flagellated. We conclude that early invasion of deeper layers of the bladder wall, independent of IBC formation, results in the establishment of reservoirs of solitary bacteria that resist elimination by antibiotics and the host innate immune response.
Publisher: Springer Science and Business Media LLC
Date: 16-11-2021
DOI: 10.1038/S41467-021-26762-2
Abstract: COVID-19 typically manifests as a respiratory illness, but several clinical reports have described gastrointestinal symptoms. This is particularly true in children in whom gastrointestinal symptoms are frequent and viral shedding outlasts viral clearance from the respiratory system. These observations raise the question of whether the virus can replicate within the stomach. Here we generate gastric organoids from fetal, pediatric, and adult biopsies as in vitro models of SARS-CoV-2 infection. To facilitate infection, we induce reverse polarity in the gastric organoids. We find that the pediatric and late fetal gastric organoids are susceptible to infection with SARS-CoV-2, while viral replication is significantly lower in undifferentiated organoids of early fetal and adult origin. We demonstrate that adult gastric organoids are more susceptible to infection following differentiation. We perform transcriptomic analysis to reveal a moderate innate antiviral response and a lack of differentially expressed genes belonging to the interferon family. Collectively, we show that the virus can efficiently infect the gastric epithelium, suggesting that the stomach might have an active role in fecal-oral SARS-CoV-2 transmission.
Publisher: Springer Science and Business Media LLC
Date: 02-06-2021
DOI: 10.1038/S41586-021-03525-Z
Abstract: The tumour suppressor APC is the most commonly mutated gene in colorectal cancer. Loss of Apc in intestinal stem cells drives the formation of adenomas in mice via increased WNT signalling
No related grants have been discovered for Hans Clevers.