Human Intestinal Tissue with Adult Stem Cell Properties Derived from Pluripotent Stem Cells

Forster, Ryan; Chiba, Kunitoshi; Schaeffer, Lorian; Regalado, Samuel G.; Lai, Christine S.; Gao, Qing; Kiani, Samira; Farin, Henner F.; Cost, Gregory J.; Chan, Andy; Rebar, Edward J.; Urnov, Fyodor D.; Gregory, Philip D.; Pachter, Lior; Jaenisch, Rudolf; Hockemeyer, Dirk

doi:10.1016/j.stemcr.2014.06.014

Cited by 14 publications

(24 citation statements)

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“…For example, neonatal surgical specimens are often severely damaged by disease and not conducive for ex vivo studies. We and others have previously demonstrated that human pluripotent stem cell derived human intestinal organoids (HIOs) closely resemble immature intestinal tissue Finkbeiner et al, 2015b;Watson et al, 2014;Forster et al, 2014;Dedhia et al, 2016;Aurora and Spence, 2016;Chin et al, 2017) and recent work has established gastrointestinal organoids as a powerful model of microbial pathogenesis at the mucosal interface McCracken et al, 2014;Forbester et al, 2015;Hill and Spence, 2017).…”

Section: Introductionmentioning

confidence: 99%

Bacterial colonization stimulates a complex physiological response in the immature human intestinal epithelium

Hill

Fields

Mukherjee

et al. 2017

Preprint

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The human gastrointestinal tract is immature at birth, yet must adapt to dramatic changes such as oral nutrition and microbial colonization. The confluence of these factors can lead to severe inflammatory disease in premature infants; however, investigating complex environment-host interactions is difficult due to limited access to immature human tissue. Here, we demonstrate that the epithelium of human pluripotent stem cell-derived human intestinal organoids is globally similar to the immature human epithelium and we utilize HIOs to investigate complex host-microbe interactions in this naïve epithelium. Our findings demonstrate that the immature epithelium is intrinsically capable of establishing a stable host-microbe symbiosis. Microbial colonization leads to complex contact and hypoxia driven responses resulting in increased antimicrobial peptide production, maturation of the mucus layer, and improved barrier function. These studies lay the groundwork for an improved mechanistic understanding of how colonization influences development of the immature human intestine.

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Section: Introductionmentioning

confidence: 99%

Bacterial colonization stimulates a complex physiological response in the immature human intestinal epithelium

Hill

Fields

Mukherjee

et al. 2017

Preprint

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“…Reporter lines using tissue-specific promoters for specific cell lineages have been described previously in hPSCs and have allowed the identification and selection of cardiomyocytes (28), hepatocytes (29), neurons (30), and pancreatic b cells (31). Although the leucine-rich, repeat-containing G-protein coupled receptor 5 (LGR5)-GFP transgenic reporter hESC line using a bacterial artificial chromosome or zinc-finger nuclease was generated and used to trace only intestinal stem cells (19,32), to our knowledge, this is the first report describing fluorescent hiPSC reporter lines that detect intestinal epithelial cells and have a potential use in the development and optimization of efficient intestinal differentiation protocols. We chose to use the ISX and Fluorescence images of hIOs-ISX eGFP using an IVIS imaging system.…”

Section: Discussionmentioning

confidence: 99%

In vitro and in vivo imaging and tracking of intestinal organoids from human induced pluripotent stem cells

et al. 2017

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Human intestinal organoids (hIOs) derived from human pluripotent stem cells (hPSCs) have immense potential as a source of intestines. Therefore, an efficient system is needed for visualizing the stage of intestinal differentiation and further identifying hIOs derived from hPSCs. Here, 2 fluorescent biosensors were developed based on human induced pluripotent stem cell (hiPSC) lines that stably expressed fluorescent reporters driven by intestine-specific gene promoters Krüppel-like factor 5 monomeric Cherry (KLF5) and intestine-specific homeobox enhanced green fluorescence protein (ISX). Then hIOs were efficiently induced from those transgenic hiPSC lines in which mCherry- or eGFP-expressing cells, which appeared during differentiation, could be identified in intact living cells in real time. Reporter gene expression had no adverse effects on differentiation into hIOs and proliferation. Using our reporter system to screen for hIO differentiation factors, we identified DMH1 as an efficient substitute for Noggin. Transplanted hIOs under the kidney capsule were tracked with fluorescence imaging (FLI) and confirmed histologically. After orthotopic transplantation, the localization of the hIOs in the small intestine could be accurately visualized using FLI. Our study establishes a selective system for monitoring the differentiation and for tracking the localization of hIOs and contributes to further improvement of cell-based therapies and preclinical screenings in the intestinal field.-Jung, K. B., Lee, H., Son, Y. S., Lee, J. H., Cho, H.-S., Lee, M.-O., Oh, J.-H., Lee, J., Kim, S., Jung, C.-R., Kim, J., Son, M.-Y. and imaging and tracking of intestinal organoids from human induced pluripotent stem cells.

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“…A powerful model system assessing these limitations are organoids. Organoids are 3D organ-like structures derived in vitro from primary tissues and adult stem cells, embryonic stem cells (ESCs) or induced pluripotent stem cells (iPSCs) [179][180][181][182][183][184][185][186][187]. These complex multicellular structures arrange through a self-organized mechanism requiring no external guidance, only appropriate niche factors and, importantly, a 3D extracellular scaffolding [55,188,189].…”

Section: Functional Scalementioning

confidence: 99%

From single cells to tissue self‐organization

Santos

Liberali

2018

The FEBS Journal

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Self‐organization is a process by which interacting cells organize and arrange themselves in higher order structures and patterns. To achieve this, cells must have molecular mechanisms to sense their complex local environment and interpret it to respond accordingly. A combination of cell‐intrinsic and cell‐extrinsic cues are decoded by the single cells dictating their behaviour, their differentiation and symmetry‐breaking potential driving development, tissue remodeling and regenerative processes. A unifying property of these self‐organized pattern‐forming systems is the importance of fluctuations, cell‐to‐cell variability, or noise. Cell‐to‐cell variability is an inherent and emergent property of populations of cells that maximize the population performance instead of the individual cell, providing tissues the flexibility to develop and maintain homeostasis in diverse environments. In this review, we will explore the role of self‐organization and cell‐to‐cell variability as fundamental properties of multicellularity—and the requisite of single‐cell resolution for its understanding. Moreover, we will analyze how single cells generate emergent multicellular dynamics observed at the tissue level ‘travelling’ across different scales: spatial, temporal and functional.

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Human Intestinal Tissue with Adult Stem Cell Properties Derived from Pluripotent Stem Cells

Cited by 14 publications

References 0 publications

Bacterial colonization stimulates a complex physiological response in the immature human intestinal epithelium

Bacterial colonization stimulates a complex physiological response in the immature human intestinal epithelium

In vitro and in vivo imaging and tracking of intestinal organoids from human induced pluripotent stem cells

From single cells to tissue self‐organization

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