A growth factor-free culture system underscores the coordination between Wnt and BMP signaling in Lgr5+ intestinal stem cell maintenance

Li, Yehua; Liu, Yuan; Liu, Bofeng; Wang, Jilian; Wei, Shuangqing; Qi, Zhengjian; Wang, Shan; Fu, Wei; Chen, Ye-Guang

doi:10.1038/s41421-018-0051-0

Cited by 47 publications

(28 citation statements)

References 27 publications

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“…After polymerization (37°C, 20 min), 250 µL organoid growth medium was added to each well. The organoid growth medium (modified from a previous publication 54 ) was prepared in DMEM high glucose GlutaMAX TM Supplement pyruvate (Thermo Fisher Scientific) with 10% fetal bovine serum (Thermo Fisher Scientific), 1% penicillin/streptomycin (Sigma-Aldrich), 1 mM HEPES (Sigma-Aldrich), 0.5 mM N-acetyl cysteine (Sigma-Aldrich), 10 µM SB431542 (Sigma-Aldrich), 10 µM CHIR99021 (Sigma-Aldrich), 10 µM Y27632 (ATCC) and 0.2 µM LDN193189 (Sigma-Aldrich). The organoid culture medium was replaced every 2-3 days.…”

Section: Organoids Culturementioning

confidence: 99%

Gut microbiota derived metabolites contribute to intestinal barrier maturation at the suckling-to-weaning transition

Beaumont

Paës²,

Mussard

et al. 2020

Gut Microbes

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In suckling mammals, the onset of solid food ingestion is coincident with the maturation of the gut barrier. This ontogenic process is driven by the colonization of the intestine by the microbiota. However, the mechanisms underlying the microbial regulation of the intestinal development in early life are not fully understood. Here, we studied the co-maturation of the microbiota (composition and metabolic activity) and of the gut barrier at the suckling-to-weaning transition by using a combination of experiments in vivo (suckling rabbit model), ex vivo (Ussing chambers) and in vitro (epithelial cell lines and organoids). The microbiota composition, its metabolic activity, para-cellular epithelial permeability and the gene expression of key components of the gut barrier shifted sharply at the onset of solid food ingestion in vivo, despite milk was still predominant in the diet at that time. We found that cecal content sterile supernatant (i.e. containing a mixture of metabolites) obtained after the onset of solid food ingestion accelerated the formation of the epithelial barrier in Caco-2 cells in vitro and our results suggested that these effects were driven by the bacterial metabolite butyrate. Moreover, the treatment of organoids with cecal content sterile supernatant partially replicated in vitro the effects of solid food ingestion on the epithelial barrier in vivo. Altogether, our results show that the metabolites produced by the microbiota at the onset of solid food ingestion contribute to the maturation of the gut barrier at the suckling-toweaning transition. Targeting the gut microbiota metabolic activity during this key developmental window might therefore be a promising strategy to promote intestinal homeostasis.

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Section: Organoids Culturementioning

confidence: 99%

Gut microbiota derived metabolites contribute to intestinal barrier maturation at the suckling-to-weaning transition

Beaumont

Paës²,

Mussard

et al. 2020

Gut Microbes

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“…ASCs-derived organoids are established under distinct culture conditions in each laboratory. To reduce the cost, cost-efficient small molecule compounds were used to replace growth factors (Li et al 2018 ;Yin et al 2014 ). Besides, homemade niche factors produced by various cell lines has been used commonly to culture organoids.…”

Section: Challengesmentioning

confidence: 99%

Organoid based personalized medicine: from bench to bedside

Tang

Cai

et al. 2020

Cell Regen

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Three-dimensional cultured organoids have become a powerful in vitro research tool that preserves genetic, phenotypic and behavioral trait of in vivo organs, which can be established from both pluripotent stem cells and adult stem cells. Organoids derived from adult stem cells can be established directly from diseased epithelium and matched normal tissues, and organoids can also be genetically manipulated by CRISPR-Cas9 technology. Applications of organoids in basic research involve the modeling of human development and diseases, including genetic, infectious and malignant diseases. Importantly, accumulating evidence suggests that biobanks of patient-derived organoids for many cancers and cystic fibrosis have great value for drug development and personalized medicine. In addition, organoids hold promise for regenerative medicine. In the present review, we discuss the applications of organoids in the basic and translational research.

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“…In the homeostatic intestinal epithelium, the hierarchical differentiation processes from the stem cells to the mature functional cells are tightly controlled by niche factors (Barker 2014 ; Clevers 2013 ; Medema and Vermeulen 2011 ; Qi and Chen 2015 ). Wnt/β-catenin signaling is essential for the maintenance of ISCs’ self-renewal and proliferation as well as Paneth cell differentiation (van Es et al 2012 ; Yin et al 2014 ); BMP/Smad signaling counteracts Wnt signaling to block ISC stemness and promotes enterocyte differentiation, as well as inducing cytostatic effects and cell death (Wang and Chen 2018 ); EGF/MAPK signaling stimulates ISC proliferation (Sato et al 2009 ), although it is dispersible in the in vitro Lgr5 + stem cell maintenance in the presence of the GSK3 inhibitor CHIR99021 and the BMP receptor inhibitor LDN-193189 (Li et al 2018 ). Notch signaling displays a different effect on ISCs – it promotes self-renewal in the presence of high Wnt signaling activity while boosting the enterocyte lineage under conditions of Wnt inhibition (Medema and Vermeulen 2011 ; Yin et al 2014 ).…”

Section: Regulation Of Cell Plasticitymentioning

confidence: 99%

Intestinal epithelial plasticity and regeneration via cell dedifferentiation

Liu

Chen

2020

Cell Regen

Self Cite

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The intestinal epithelium possesses a great capacity of self-renewal under normal homeostatic conditions and of regeneration upon damages. The renewal and regenerative processes are driven by intestinal stem cells (ISCs), which reside at the base of crypts and are marked by Lgr5. As Lgr5+ ISCs undergo fast cycling and are vulnerable to damages, there must be other types of cells that can replenish the lost Lgr5+ ISCs and then regenerate the damage epithelium. In addition to Lgr5+ ISCs, quiescent ISCs at the + 4 position in the crypt have been proposed to convert to Lgr5+ ISCs during regeneration. However, this “reserve stem cell” model still remains controversial. Different from the traditional view of a hierarchical organization of the intestinal epithelium, recent works support the dynamic “dedifferentiation” model, in which various cell types within the epithelium can de-differentiate to revert to the stem cell state and then regenerate the epithelium upon tissue injury. Here, we provide an overview of the cell identity and features of two distinct models and discuss the possible mechanisms underlying the intestinal epithelial plasticity.

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A growth factor-free culture system underscores the coordination between Wnt and BMP signaling in Lgr5+ intestinal stem cell maintenance

Cited by 47 publications

References 27 publications

Gut microbiota derived metabolites contribute to intestinal barrier maturation at the suckling-to-weaning transition

Gut microbiota derived metabolites contribute to intestinal barrier maturation at the suckling-to-weaning transition

Organoid based personalized medicine: from bench to bedside

Intestinal epithelial plasticity and regeneration via cell dedifferentiation

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