The Intestinal Stem Cell Niche: Homeostasis and Adaptations

Santos, António J. M.; Lo, Yuan–Hung; Mah, Amanda T.; Kuo, Calvin J.

doi:10.1016/j.tcb.2018.08.001

Cited by 205 publications

(138 citation statements)

References 149 publications

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“…However, studies on Lgr5 + crypt basal cells in the small intestine have provided insight into ISC maintenance and regulation by factors from the stem cell niche (134). A multitude of signaling pathways control ISC activity and function, including Wnt, BMP, and Hh and Notch signaling (135). Most critically, a gradient of Wnt activity along the crypt axis maintains ISC regenerative capacity (136)(137)(138)(139)(140)(141)(142), and its loss leads to complete ablation of intestinal crypts.…”

Section: Mammalian Intestinal Stem Cellsmentioning

confidence: 99%

Intestinal Stem Cell Aging: Origins and Interventions

Jasper¹

2020

Annu. Rev. Physiol.

127

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Regenerative processes that maintain the function of the gastrointestinal (GI) epithelium are critical for health and survival of multicellular organisms. In insects and vertebrates, intestinal stem cells (ISCs) regenerate the GI epithelium. ISC function is regulated by intrinsic, local, and systemic stimuli to adjust regeneration to tissue demands. These control mechanisms decline with age, resulting in significant perturbation of intestinal homeostasis. Processes that lead to this decline have been explored intensively in Drosophila melanogaster in recent years and are now starting to be characterized in mammalian models. This review presents a model for age-related regenerative decline in the fly intestine and discusses recent findings that start to establish molecular mechanisms of age-related decline of mammalian ISC function. 203 Annu. Rev. Physiol. 2020.82:203-226. Downloaded from www.annualreviews.org Access provided by 44.224.250.200 on 07/08/20. For personal use only.

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Section: Mammalian Intestinal Stem Cellsmentioning

confidence: 99%

Intestinal Stem Cell Aging: Origins and Interventions

Jasper¹

2020

Annu. Rev. Physiol.

127

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“…This might be due to fact that BCL9/9L loss in the intestinal epithelium only transiently induces downregulation of IESC markers [12][13][14][15] . However, compelling evidence has recently been provided that the intestinal IESC niche is readily regenerated upon perturbations, as differentiated cells can revert to stem cells [40][41][42][43] . Epithelial plasticity can thus mask the effects of loss of function studies of proteins, such as BCL9/9L, whose contribution to intestinal homeostasis only becomes apparent when the epithelial stem cell niche is challenged.…”

Section: Discussionmentioning

confidence: 99%

Discrete regulation of β-catenin-mediated transcription governs identity of intestinal epithelial stem cells

Borrelli

Valenta

Handler

et al. 2020

Preprint

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The homeostasis of the gut epithelium relies upon continuous renewal and proliferation of crypt-resident intestinal epithelial stem cells (IESCs). Wnt/β-catenin signaling is required for IESC maintenance, however, it remains unclear how this pathway selectively governs the identity and proliferative decisions of IESCs. Here, we demonstrate that C-terminally-recruited transcriptional co-factors of β-catenin act as all-or-nothing regulators of Wnt-target gene expression. Blocking their interactions with β-catenin rapidly induces loss of IESCs and intestinal homeostasis. Conversely, N-terminally recruited co-factors fine-tune β-catenin's transcriptional output to ensure proper self-renewal and proliferative behaviour of IESCs. Impairment of N-terminal interactions triggers transient hyperproliferation of IESCs, eventually resulting in exhaustion of the self-renewing stem cell pool. IESC mis-differentiation, accompanied by intrinsic and extrinsic stress signalling results in a process resembling aberrant "villisation" of intestinal crypts. Our data suggest that IESC-specific Wnt/β-catenin output requires discrete regulation of transcription by transcriptional co-factors. Results Attenuation of N-vs. C-terminal β-catenin transcriptional outputs has contrasting effects on intestinal homeostasisWe previously generated transgenic β-catenin (Ctnnb1) alleles harboring mutations that prevent interactions with N-or C-terminal transcriptional co-factors (NTFs and CTFs, respectively) 7 . The D164A mutation abrogates interaction with NTFs, the ∆C truncation abrogates the interaction with the CTFs (Fig. 1a). To overcome embryonic lethality of these alleles, we used compound heterozygous mice carrying one mutant and one conditional βcatenin allele (Extended Data Fig. 1a). Similarly to constitutively hemizygous Ctnnb1 KO/wt mice, Ctnnb1 D164A/flox and Ctnnb1 ∆C/flox animals show no overt abnormalities, indicating haplosufficiency of β-catenin for the maintenance of intestinal homeostasis. Combination with the villin-CreER T2 driver 16 enables the inducible deletion of the conditional β-catenin allele (Ctnnb1 flox ) specifically in the intestinal epithelium, thus leaving the Wnt-transcriptional outputs solely under the control of mutant β-catenin (D164A or ∆C). While villin-CreER T2 ;Ctnnb1 wt/flox (control) mice are perfectly viable and indistinguishable from homozygous wild type animals, the presence of only mutant β-catenin is lethal: villin-CreER T2 ;Ctnnb1 ∆C/flox (∆C) animals exhibit atrophic crypts at 4d post Cre induction (pi) (Extended Data Fig. 1b). This is in accordance with our previous results in villin-CreER T2 ;Ctnnb1 dm/flox animals, which express double mutant (dm) β-catenin harboring both N-and C-terminal mutations 17 . Unlike dm and ∆C animals, villin-CreER T2 ;Ctnnb1 D164A/flox (D164A) animals only reach humane endpoint at 7d pi, as they suffer from severe colitis (Extended Data Fig. 1c). The different intestinal phenotypes that arise upon blocking C-or N-terminal transcriptional outputs of β-catenin are consist...

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“…For instance, the intestinal SCN influences stem cell behavior to govern intestinal homeostasis under physiological and pathological conditions [13] and plays a pivotal role in responses to infection [41,61]. The intestinal microbiota and their by-products shape the architecture of the intestinal epithelia [62,63], and influence the intestinal SCN renewal and differentiation, through stimulation of stromal, epithelial, and immune cells [5,63]. Moreover, during infection with intestinal pathogens, the microbiota influences their establishment in the tissue and the development of immune responses [40,64].…”

Section: Complementing the System For Future Applicationsmentioning

confidence: 99%

“…The anaerobic nature of the majority of the members of the intestinal microbiota complicates its co-culture in 2D organoid systems that grow under normal oxygen concentrations [5,75]. However, introduction of some oxygen-tolerant microbiota members (and their components and by-products), in organoid cultures and other intestinal models, has allowed their influence on the intestinal SCN to be studied [62,73,75].…”

Section: Complementing the System For Future Applicationsmentioning

confidence: 99%

Organoids – New Models for Host–Helminth Interactions

Duque-Correa

Maizels

Grencis

et al. 2020

Trends in Parasitology

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Organoids are multicellular culture systems that replicate tissue architecture and function, and are increasingly used as models of viral, bacterial, and protozoan infections. Organoids have great potential to improve our current understanding of helminth interactions with their hosts and to replace or reduce the dependence on using animal models. In this review, we discuss the applicability of this technology to helminth infection research, including strategies of co-culture of helminths or their products with organoids and the challenges, advantages, and drawbacks of the use of organoids for these studies. We also explore how complementing organoid systems with other cell types and components may allow more complex models to be generated in the future to further investigate helminth-host interactions.

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The Intestinal Stem Cell Niche: Homeostasis and Adaptations

Cited by 205 publications

References 149 publications

Intestinal Stem Cell Aging: Origins and Interventions

Intestinal Stem Cell Aging: Origins and Interventions

Discrete regulation of β-catenin-mediated transcription governs identity of intestinal epithelial stem cells

Organoids – New Models for Host–Helminth Interactions

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