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Author

Laurens G. van der Flier

Bio: Laurens G. van der Flier is an academic researcher from Utrecht University. The author has contributed to research in topics: Stem cell & LGR5. The author has an hindex of 10, co-authored 10 publications receiving 5465 citations. Previous affiliations of Laurens G. van der Flier include University Medical Center Utrecht & Royal Netherlands Academy of Arts and Sciences.

Papers
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Journal ArticleDOI
01 Oct 2010-Cell
TL;DR: Quantitative analysis shows that stem cell turnover follows a pattern of neutral drift dynamics, consistent with a model in which the resident stem cells double their numbers each day and stochastically adopt stem or TA fates.

1,708 citations

Journal ArticleDOI
TL;DR: In this review, the identification of intestinal stem cells is described and genetic studies that have helped to elucidate those signals important for progenitor cells to differentiate into one of the specialized intestinal epithelial cell types are discussed.
Abstract: The mammalian intestine is covered by a single layer of epithelial cells that is renewed every 4-5 days. This high cell turnover makes it a very attractive and comprehensive adult organ system for the study of cell proliferation and differentiation. The intestine is composed of proliferative crypts, which contain intestinal stem cells, and villi, which contain differentiated specialized cell types. Through the recent identification of Lgr5, an intestinal stem cell marker, it is now possible to visualize stem cells and study their behavior and differentiation in a much broader context. In this review we describe the identification of intestinal stem cells. We also discuss genetic studies that have helped to elucidate those signals important for progenitor cells to differentiate into one of the specialized intestinal epithelial cell types. These studies describe a genetic hierarchy responsible for cell fate commitment in normal gut physiology. Where relevant we also mention aberrant deregulation of these molecular pathways that results in colon cancer.

1,539 citations

Journal ArticleDOI
06 Mar 2009-Cell
TL;DR: The combined results from these gain- and loss-of-function experiments imply that Ascl2 controls intestinal stem cell fate, and this gene signature is the Wnt target Achaete scute-like 2 (Ascl2).

659 citations

Journal ArticleDOI
TL;DR: An exhaustive array-based analysis of a core target gene program, the intestinal Wnt/TCF signature gene set, which is responsible for the transformation of human intestinal epithelial cells, was performed in colorectal cancer cell lines carrying an inducible block of the Wnt cascade.

480 citations

Journal ArticleDOI
TL;DR: Using Cre-mediated genetic tracng, it is demonstrated that Lgr5 marks long-lived, multiotent stem cells, and it is proposed that human OLFM4 is enriched in human small intestine and colon.

471 citations


Cited by
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Journal ArticleDOI
Donna M. Muzny1, Matthew N. Bainbridge1, Kyle Chang1, Huyen Dinh1  +317 moreInstitutions (24)
19 Jul 2012-Nature
TL;DR: Integrative analyses suggest new markers for aggressive colorectal carcinoma and an important role for MYC-directed transcriptional activation and repression.
Abstract: To characterize somatic alterations in colorectal carcinoma, we conducted a genome-scale analysis of 276 samples, analysing exome sequence, DNA copy number, promoter methylation and messenger RNA and microRNA expression. A subset of these samples (97) underwent low-depth-of-coverage whole-genome sequencing. In total, 16% of colorectal carcinomas were found to be hypermutated: three-quarters of these had the expected high microsatellite instability, usually with hypermethylation and MLH1 silencing, and one-quarter had somatic mismatch-repair gene and polymerase e (POLE) mutations. Excluding the hypermutated cancers, colon and rectum cancers were found to have considerably similar patterns of genomic alteration. Twenty-four genes were significantly mutated, and in addition to the expected APC, TP53, SMAD4, PIK3CA and KRAS mutations, we found frequent mutations in ARID1A, SOX9 and FAM123B. Recurrent copy-number alterations include potentially drug-targetable amplifications of ERBB2 and newly discovered amplification of IGF2. Recurrent chromosomal translocations include the fusion of NAV2 and WNT pathway member TCF7L1. Integrative analyses suggest new markers for aggressive colorectal carcinoma and an important role for MYC-directed transcriptional activation and repression.

6,883 citations

Journal ArticleDOI
TL;DR: Some key aspects of Wnt/beta-catenin signaling in human diseases including congenital malformations, cancer, and osteoporosis are highlighted, and potential therapeutic implications are discussed.

4,926 citations

Journal ArticleDOI
25 Oct 2007-Nature
TL;DR: The expression pattern of Lgr5 suggests that it marks stem cells in multiple adult tissues and cancers, suggesting that it represents the stem cell of the small intestine and colon.
Abstract: The intestinal epithelium is the most rapidly self-renewing tissue in adult mammals. It is currently believed that four to six crypt stem cells reside at the +4 position immediately above the Paneth cells in the small intestine; colon stem cells remain undefined. Lgr5 (leucine-rich-repeat-containing G-protein-coupled receptor 5, also known as Gpr49) was selected from a panel of intestinal Wnt target genes for its restricted crypt expression. Here, using two knock-in alleles, we reveal exclusive expression of Lgr5 in cycling columnar cells at the crypt base. In addition, Lgr5 was expressed in rare cells in several other tissues. Using an inducible Cre knock-in allele and the Rosa26-lacZ reporter strain, lineage-tracing experiments were performed in adult mice. The Lgr5-positive crypt base columnar cell generated all epithelial lineages over a 60-day period, suggesting that it represents the stem cell of the small intestine and colon. The expression pattern of Lgr5 suggests that it marks stem cells in multiple adult tissues and cancers.

4,918 citations

Journal ArticleDOI
TL;DR: An international consortium dedicated to large-scale data sharing and analytics across expert groups is formed, showing marked interconnectivity between six independent classification systems coalescing into four consensus molecular subtypes (CMSs) with distinguishing features.
Abstract: Colorectal cancer (CRC) is a frequently lethal disease with heterogeneous outcomes and drug responses. To resolve inconsistencies among the reported gene expression-based CRC classifications and facilitate clinical translation, we formed an international consortium dedicated to large-scale data sharing and analytics across expert groups. We show marked interconnectivity between six independent classification systems coalescing into four consensus molecular subtypes (CMSs) with distinguishing features: CMS1 (microsatellite instability immune, 14%), hypermutated, microsatellite unstable and strong immune activation; CMS2 (canonical, 37%), epithelial, marked WNT and MYC signaling activation; CMS3 (metabolic, 13%), epithelial and evident metabolic dysregulation; and CMS4 (mesenchymal, 23%), prominent transforming growth factor-β activation, stromal invasion and angiogenesis. Samples with mixed features (13%) possibly represent a transition phenotype or intratumoral heterogeneity. We consider the CMS groups the most robust classification system currently available for CRC-with clear biological interpretability-and the basis for future clinical stratification and subtype-based targeted interventions.

3,351 citations

Journal ArticleDOI
26 May 2011-Neuron
TL;DR: Major advances in understanding of adult mammalian neurogenesis in the dentate gyrus of the hippocampus and from the subventricular zone of the lateral ventricle, the rostral migratory stream to the olfactory bulb are reviewed.

2,308 citations