Mature enteroendocrine cells contribute to basal and pathological stem cell dynamics in the small intestine

Sei, Yoshitatsu; Feng, Jianying; Samsel, Leigh; White, Ayla O.; Zhao, Xilin; Yun, Sajung; Citrin, Deborah E.; McCoy, J. Philip; Sundaresan, Sinju; Hayes, Michael M.; Merchant, Juanita L.; Leiter, Andrew B.; Wank, Stephen A.

doi:10.1152/ajpgi.00036.2018

Cited by 32 publications

(24 citation statements)

References 59 publications

(110 reference statements)

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“…Both LGR5 + and Bmi1 + cells can generate intestinal organoids in culture (113). After ablation of LGR5 + cells, Bmi1 + cells can restore the crypt base cell population, providing evidence for significant plasticity of cell identities in the crypt (15), a concept that has been supported by findings that the crypt base can be repopulated by other cell types as well, including differentiated endocrine and Paneth cells (15,16,107,(114)(115)(116)(117). A recent study has also proposed the presence of a distinct revival stem cell population that can repopulate the crypt in conditions of severe damage (118).…”

Section: Mammalian Intestinal Stem Cellsmentioning

confidence: 95%

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: 95%

Intestinal Stem Cell Aging: Origins and Interventions

Jasper¹

2020

Annu. Rev. Physiol.

127

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“…Thus, the intrinsic Cdc42-MAPK program is required for intestinal epithelial regeneration, and elevating this signaling cascade is capable of initiating protection from genotoxic injury. cell populations in response to injury-induced ISC loss (3,(12)(13)(14)(15)(16)(17)(18)(19)(20)(21). The interactive complexity of intrinsic and extrinsic epithelial signaling that confers remarkable tissue plasticity remains both poorly defined and of important biomedical impact.…”

Section: Introductionmentioning

confidence: 99%

Elevating EGFR-MAPK program by a nonconventional Cdc42 enhances intestinal epithelial survival and regeneration

Zhang¹,

Bandyopadhyay²,

Araújo³

et al. 2020

JCI Insight

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Results Cdc42 is indispensable for enteroid survival. Cdc42 ΔIEC mice with constitutive IEC-specific Cdc42 ablation via Villin-Cre were viable (28). However, crypts isolated from Cdc42 ΔIEC mice did not develop into enteroids in medium containing EGF, Noggin, and R-Spondin (ENR). Within 24 hours after seeding, all Cdc42 ΔIEC crypts were growth arrested (Supplemental Figure 1A; supplemental material available online with this article; https://doi.org/10.1172/jci.insight.135923DS1). Because this growth deficit could be secondary to abnormal development by Cdc42 ΔIEC intestinal epithelia, we used Villin-CreER to delete Cdc42 from mature Cdc42 fl/fl Villin-CreER (Cdc42 iKO) enteroids. Forty-eight hours after 4-hydroxytamoxifen (4-OHT) addition, the epithelial buds in over 60% of Cdc42 iKO enteroids regressed, with cell death and cellular debris (Figure 1, A and B; and Supplemental Figure 1B). After 72 hours, 95% of Cdc42 iKO enteroids accumulated significant amounts of propidium iodide, indicative of massive cell death (Figure 1B), which was further corroborated by elevated numbers of cleaved caspase-3-positive cells (Figure 1C) and a loss of over 90% live enteroid cells quantified by the CellTiter-Glo 3D Cell Viability Assay (Figure 1D). Viable enteroids were not detected at 5 days after Cdc42 deletion, and the growth of WT (WT) enteroids was not affected by 4-OHT over this time period (Figure 1, AD). Thus, maintenance of enteroid growth in ENR medium absolutely was dependent upon Cdc42 expression. Cdc42 is required for and sufficient to promote EGF/MAPK signaling ex vivo. We first suspected a disrupted Wnt signaling in Cdc42-deficient enteroids; therefore, we tried to rescue the growth of Cdc42-deficient enteroids by enhancing canonical Wnt signaling via the glycogen synthase kinase-3β inhibitor CHIR99021. However, we failed to observe a reversing effect on death (Supplemental Figure 1C), suggesting that canonical Wnt pathway was not the primary pathway affected by Cdc42 deficiency. Treating serum-starved human Caco2 cells with EGF ligands (EGF and TGF-α), canonical Wnt ligand (Wnt3a), or Noggin activated Cdc42 GTPase activities within minutes (Supplemental Figure 1D), suggesting that multiple ISC growth factors could act through Cdc42 machinery. These results led us to conduct an unbiased proteomic search for Cdc42-regulated survival signaling. Parallel mass spectrometry was done on canonical Cdc42 (V1) and its splicing variant (V2), both of which were 3xFlag-tagged and transfected into HEK293 cells. Proteomic analysis of Cdc42 V1 and V2 immunoprecipitates identified an overlapped interactome, where the 5 top functional clusters mapped to cell cycle, cell division, clathrin-coated endocytosis, mitosis, and MAPK cascade components (P < 0.001, Figure 1E and Supplemental Figure 1, E and F). The identification of a clathrin and MAPK interactome components suggests that Cdc42 may control MAPK activation through clathrin-dependent endocytic EGFR signaling (37-41). EGF stimulates rapid receptor-mediated endocytosis that ...

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“…EECs are sufficient to contribute to homeostatic and repair activities in the mouse in cell populations 22 not expressing the broad stem cell factor leucine-rich repeat-containing G-protein coupled receptor 5 23 (Lgr5) suggesting EEC may be a source of resident quiescent stem cells for this tissue. Lgr5 + intestinal 24 stem cells show a bias towards differentiation into EEC morphologies in vitro suggesting EECs may 25 have developmental potential within the intestine for proliferation and stem cell function (Basak et al, 26 2017;Buczacki et al, 2013) (Sei et al, 2018). Zebrafish do not have a Lgr5 orthologue for direct 27 comparison, however we show that celsr1a marks a similar population of secretory EECs and that loss 28 of celsr1a function leads to a loss of homeostasis and decreased progenitor cell number.…”

Section: Role Of Celsr1a In Regulating Progenitor Cell Populations 10mentioning

confidence: 74%

“…7J). Previous work has identified EECs as 20 being a source of quiescent stem cells in the adult mouse intestine (Basak et al, 2017;Sei et al, 2018). 21…”

Section: Role Of Celsr1a In Regulating Progenitor Cell Populations 10mentioning

confidence: 99%

Celsr1a is essential for tissue homeostasis and onset of aging phenotypes in the zebrafish

Barton

Henke

et al. 2019

Preprint

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The use of experimental genetics has been invaluable in defining the complex mechanisms by which aging and longevity are regulated. Zebrafish, while a prominent model for understanding the genetic basis of vertebrate development, have not been used systematically to address questions of how and why we age. In a mutagenesis screen focusing on late developmental phenotypes, we identified a new mutant, fruehrentner, that displays typical signs of aging already at young adult stages. We find that the phenotype is due to loss-of-function in the non-classical cadherin EGF LAG seven-pass G-type receptor 1a (celsr1a). The premature aging phenotype is not associated with increased cellular senescence or decreased telomere length but is a result of a broad failure to maintain progenitor cell populations in tissues. Through the analysis of a knockin reporter line, we find that celsr1a GFP is expressed broadly in early development but becomes restricted during maturation. We show that celsr1a is essential for maintenance of stem cell progenitors and leads to shifts in cell fate determination. Although celsr1a has many signaling functions including establishment of polarity within tissues, we show that caloric restriction can ameliorate the effect of celsr1a on lifespan in part through compensatory upregulation of celsr1 paralogues. These data suggest that celsr1a function helps to mediate stem cell maintenance during maturation and homeostasis of tissues and thus regulates the onset or expressivity of aging phenotypes.

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Mature enteroendocrine cells contribute to basal and pathological stem cell dynamics in the small intestine

Cited by 32 publications

References 59 publications

Intestinal Stem Cell Aging: Origins and Interventions

Intestinal Stem Cell Aging: Origins and Interventions

Elevating EGFR-MAPK program by a nonconventional Cdc42 enhances intestinal epithelial survival and regeneration

Celsr1a is essential for tissue homeostasis and onset of aging phenotypes in the zebrafish

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