Single Lgr5 stem cells build crypt-villus structures in vitro without a mesenchymal niche

Sato, Toshiro; Vries, Robert G. J.; Snippert, Hugo J.G.; Wetering, Marc van de; Barker, Nick; Stange, Daniel E.; Es, Johan H. van; Abo, Arie; Kujala, Pekka; Peters, Peter J.; Clevers, Hans

doi:10.1038/nature07935

Cited by 5,810 publications

(6,237 citation statements)

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“…To determine whether some of the Ret transcript detected in these whole‐tissue samples originated from the intestinal epithelium and to further investigate its developmental expression, we derived epithelial cultures from both developing and mature small intestinal tissue. Epithelial cells from the adult small intestine of mice can be cultured ex vivo as budding organoids with distinct proliferative and differentiated domains (Sato et al , 2009). If epithelial cells are instead derived from the foetal epithelium or the proximal region of the neonatal intestine, they grow like spheroids (foetal enterospheres—FEnS) when subject to the same treatment.…”

Section: Resultsmentioning

confidence: 99%

Ret receptor tyrosine kinase sustains proliferation and tissue maturation in intestinal epithelia

et al. 2017

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Expression of the Ret receptor tyrosine kinase is a defining feature of enteric neurons. Its importance is underscored by the effects of its mutation in Hirschsprung disease, leading to absence of gut innervation and severe gastrointestinal symptoms. We report a new and physiologically significant site of Ret expression in the intestine: the intestinal epithelium. Experiments in Drosophila indicate that Ret is expressed both by enteric neurons and adult intestinal epithelial progenitors, which require Ret to sustain their proliferation. Mechanistically, Ret is engaged in a positive feedback loop with Wnt/Wingless signalling, modulated by Src and Fak kinases. We find that Ret is also expressed by the developing intestinal epithelium of mice, where its expression is maintained into the adult stage in a subset of enteroendocrine/enterochromaffin cells. Mouse organoid experiments point to an intrinsic role for Ret in promoting epithelial maturation and regulating Wnt signalling. Our findings reveal evolutionary conservation of the positive Ret/Wnt signalling feedback in both developmental and homeostatic contexts. They also suggest an epithelial contribution to Ret loss‐of‐function disorders such as Hirschsprung disease.

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Section: Resultsmentioning

confidence: 99%

Ret receptor tyrosine kinase sustains proliferation and tissue maturation in intestinal epithelia

et al. 2017

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“…26 Cultures were established with crypts from Control and NleVilcKO mice 1 h following the last tamoxifen injection. Control crypts grew into organoids within 3 days of culture, and the vast majority had developed more than 3 buds after 6 days.…”

Section: Resultsmentioning

confidence: 99%

Ribosome biogenesis dysfunction leads to p53-mediated apoptosis and goblet cell differentiation of mouse intestinal stem/progenitor cells

et al. 2015

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International audienceRibosome biogenesis is an essential cellular process. Its impairment is associated with developmental defects and increased risk of cancer. The in vivo cellular responses to defective ribosome biogenesis and the underlying molecular mechanisms are still incompletely understood. In particular, the consequences of impaired ribosome biogenesis within the intestinal epithelium in mammals have not been investigated so far. Here we adopted a genetic approach to investigate the role of Notchless (NLE), an essential actor of ribosome biogenesis, in the adult mouse intestinal lineage. Nle deficiency led to defects in the synthesis of large ribosomal subunit in crypts cells and resulted in the rapid elimination of intestinal stem cells and progenitors through distinct types of cellular responses, including apoptosis, cell cycle arrest and biased differentiation toward the goblet cell lineage. Similar observations were made using the rRNA transcription inhibitor CX-5461 on intestinal organoids culture. Importantly, we found that p53 activation was responsible for most of the cellular responses observed, including differentiation toward the goblet cell lineage. Moreover, we identify the goblet cell-specific marker Muc2 as a direct transcriptional target of p53. Nle-deficient ISCs and progenitors disappearance persisted in the absence of p53, underlying the existence of p53-independent cellular responses following defective ribosome biogenesis. Our data indicate that NLE is a crucial factor for intestinal homeostasis and provide new insights into how perturbations of ribosome biogenesis impact on cell fate decisions within the intestinal epithelium

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“…Furthermore, GVHD caused the most significant damage to the intestinal stem cells (ISC), which was even more pronounced in case of host IL‐22 deficiency. ISC are located at the base of the intestinal epithelial crypts between Paneth cells and ISC are able to generate the whole crypt‐villus structures in vivo and in vitro 34. The authors identified IL‐22R expression on ISC and epithelial progenitor cells, which—together with mature intestinal epithelial cells—produce antimicrobial proteins Reg3β and Reg3γ in response to IL‐22 29.…”

Section: Potential Of Il‐22 Producing Ilc3 In Gvhd Therapymentioning

confidence: 99%

Innate Lymphoid Cells in Graft-Versus-Host Disease

Kónya

Mjösberg

2015

American Journal of Transplantation

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Innate lymphoid cells (ILC) are lymphocytes lacking rearranged antigen receptors such as those expressed by T and B cells. ILC are important effector and regulatory cells of the innate immune system, controlling lymphoid organogenesis, tissue inflammation, and homeostasis. The family of ILC consists of cytotoxic NK cells and the more recently described noncytotoxic group 1, 2, and 3 ILC. The classification of noncytotoxic ILC—in many aspects—mirrors that of T helper cells, which is based on the expression of master transcription factors and signature cytokines specific for each subset. The IL‐22 producing RORγt+ ILC3 subset was recently found to be critical in the prevention of intestinal graft‐versus‐host disease (GVHD) following allogeneic hematopoietic cell transplantation (HCT) via strengthening the intestinal mucosal barrier. In this review, we summarize the current view of the immunological functions of human noncytotoxic ILC subsets and discuss the potentially beneficial features of IL‐22 producing ILC3 in improving allo‐HCT efficacy by attenuating susceptibility to GVHD. In addition, we explore the possibility of other ILC subsets playing a role in GVHD.

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Single Lgr5 stem cells build crypt-villus structures in vitro without a mesenchymal niche

Cited by 5,810 publications

References 29 publications

Ret receptor tyrosine kinase sustains proliferation and tissue maturation in intestinal epithelia

Ret receptor tyrosine kinase sustains proliferation and tissue maturation in intestinal epithelia

Ribosome biogenesis dysfunction leads to p53-mediated apoptosis and goblet cell differentiation of mouse intestinal stem/progenitor cells

Innate Lymphoid Cells in Graft-Versus-Host Disease

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