Interleukin-2 induces the in vitro maturation of human pluripotent stem cell-derived intestinal organoids

Jung, Kwang Bo; Lee, Hana; Son, Ye Seul; Lee, Mi‐Ok; Kim, Young-Dae; Oh, Soo Jin; Kwon, Ohman; Cho, Sunwha; Cho, Hyun Soo; Kim, Dae‐Soo; Oh, Jung‐Hwa; Zilbauer, Matthias; Kim, Jung Min; Jung, Cho‐Rok; Kim, Jang Hwan; Son, Mi‐Young

doi:10.1038/s41467-018-05450-8

Cited by 92 publications

(106 citation statements)

References 50 publications

(57 reference statements)

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“…IL‐2 is involved in cell fibrosis, immunoregulation, development and other biological behaviors via activation of the STAT3 and NK‐κB signaling pathways (Jung et al., ; Luo et al., ; Mitrokhin, Gorbacheva, Mladenov, & Kamkin, ; Park et al., ; Wu et al., ). In our study, IL‐2 could activate STAT3 and NK‐κB signaling pathways.…”

Section: Discussionmentioning

confidence: 99%

Interleukin‐2 induces extracellular matrix synthesis and TGF‐β2 expression in retinal pigment epithelial cells

Jing

Wen

et al. 2019

Dev Growth Differ

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Macular fibrosis is a vital obstacle of vision acuity improvement of age‐related macular degeneration patients. This study was to investigate the effects of interleukin 2 (IL‐2) on epithelial‐mesenchymal transition (EMT), extracellular matrix (ECM) synthesis and transforming growth factor β2 (TGF‐β2) expression in retinal pigment epithelial (RPE) cells. 10 μg/L IL‐2 was used to induce fibrosis in RPE cells for various times. Western blot was used to detect the EMT marker α‐smooth muscle actin (α‐SMA), ECM markers fibronectin (Fn) and type 1 collagen (COL‐1), TGF‐β2, and the activation of the JAK/STAT3 and NF‐κB signaling pathway. Furthermore, JAK/STAT3 and NF‐κB signaling pathways were specifically blocked by WP1066 or BAY11‐7082, respectively, and the expression of α‐SMA, COL‐1, Fn and TGF‐β2 protein were detected. Wound healing and Transwell assays were used to measure cell migration ability of IL‐2 with or without WP1066 or BAY11‐7082. After induction of IL‐2, the expressions of Fn, COL‐1, TGF‐β2 protein were significantly increased, and this effect was correlated with IL‐2 treatment duration, while α‐SMA protein expression did not change significantly. Both WP1066 and BAY11‐7082 could effectively downregulate the expression of Fn, COL‐1 and TGF‐β2 induced by IL‐2. What's more, both NF‐κB and JAK/STAT3 inhibitors could suppress the activation of the other signaling pathway. Additionally, JAK/STAT3 inhibitor WP1066 and NF‐κB inhibitor BAY 11‐7082 could obviously decrease RPE cells migration capability induced by IL‐2. IL‐2 promotes cell migration, ECM synthesis and TGF‐β2 expression in RPE cells via JAK/STAT3 and NF‐κB signaling pathways, which may play an important role in proliferative vitreoretinopathy.

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Section: Discussionmentioning

confidence: 99%

Interleukin‐2 induces extracellular matrix synthesis and TGF‐β2 expression in retinal pigment epithelial cells

Jing

Wen

et al. 2019

Dev Growth Differ

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“…This indicated that the immune system is a component of the intestinal stem cell niche and regulates intestinal regeneration. In a PSC-derived intestinal organoid system, coculture with T lymphocytes and treatment with interleukin-2 (IL-2) led to in vitro maturation of intestinal organoids that retained fetal intestinal properties 80 . Jung et al confirmed that IL-2, the most abundant cytokine secreted by T lymphocytes, produces PSC-derived intestinal organoids with a gene expression profile and functionality that is similar to that of adult intestinal tissue 80 .…”

Section: Intestinal Organoids Integrated With Stromal Cellsmentioning

confidence: 99%

“…In a PSC-derived intestinal organoid system, coculture with T lymphocytes and treatment with interleukin-2 (IL-2) led to in vitro maturation of intestinal organoids that retained fetal intestinal properties 80 . Jung et al confirmed that IL-2, the most abundant cytokine secreted by T lymphocytes, produces PSC-derived intestinal organoids with a gene expression profile and functionality that is similar to that of adult intestinal tissue 80 . These results indicate that soluble factors secreted by immune cells have a profound effect on the regeneration and maturation of intestinal tissue and that inclusion of immune cell interactions is an effective strategy for overcoming the limitations of functionally immature PSC-derived intestinal organoids.…”

Section: Intestinal Organoids Integrated With Stromal Cellsmentioning

confidence: 99%

Gastrointestinal tract modeling using organoids engineered with cellular and microbiota niches

2020

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The recent emergence of organoid technology has attracted great attention in gastroenterology because the gastrointestinal (GI) tract can be recapitulated in vitro using organoids, enabling disease modeling and mechanistic studies. However, to more precisely emulate the GI microenvironment in vivo, several neighboring cell types and types of microbiota need to be integrated into GI organoids. This article reviews the recent progress made in elucidating the crosstalk between GI organoids and components of their microenvironment. We outline the effects of stromal cells (such as fibroblasts, neural cells, immune cells, and vascular cells) on the gastric and intestinal epithelia of organoids. Because of the important roles that microbiota play in the physiology and function of the GI tract, we also highlight interactions between organoids and commensal, symbiotic, and pathogenic microorganisms and viruses. GI organoid models that contain niche components will provide new insight into gastroenterological pathophysiology and disease mechanisms.

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“…Conversely, differentiation 18 and maturation 19 of human iPSC-derived intestinal organoids (HIO) provides greater control over genetics and environment, which are necessary for modelling a multifactorial disease. Following 7-day co-culture with HIO, hILC1 maintained their phenotypic response to activation, upregulating IFNG but not IL22 (Fig.…”

Section: Ibd-patient Ilc1 Upregulate Intestinal Cd44v6mentioning

confidence: 99%

ILC1-derived TGFβ1 drives intestinal remodelling

Jowett

Norman

et al. 2020

Preprint

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Organoids can shed light on the dynamic interplay between complex tissues and rare cell types within a controlled microenvironment. Here, we developed gut organoid co-cultures with type-1 innate lymphoid cells (ILC1) to dissect the impact of their accumulation in inflamed intestines.We demonstrate for the first time that murine and human ILC1 secrete TGFβ1, driving expansion of CD44v6 + epithelial crypts. ILC1 additionally express MMP9 and drive gene signatures indicative of extracellular matrix remodelling. We therefore encapsulated human epithelial-mesenchymal intestinal organoids in MMP-sensitive, synthetic hydrogels designed to form efficient networks at low polymer concentrations. Harnessing this defined system, we demonstrate that ILC1 drive matrix softening and stiffening, which we suggest occurs through balanced matrix degradation and deposition. Our platform enabled us to elucidate previously undescribed interactions between ILC1 and their microenvironment, which suggest that they may exacerbate fibrosis and tumour growth when enriched in inflamed patient tissues. MainIntestinal epithelial cells (IEC) 1 interact with innate lymphoid cells (ILC) 2 to form a dynamic barrier between organisms and their environment. Together, they are capable of rapidly responding to danger and damage in an antigen non-specific manner. For instance, type-3 ILC3 secrete Interleukin-22 (IL-22, Il22 ) in response to extracellular pathogens, which promotes anti-microbial peptide secretion and proliferation of Lgr5 + CD44 + intestinal stem cells 3 .Conversely, type-1 ILC express Interferon-gamma (IFNγ, Ifng ) in response to intracellular pathogens, and are comprised of circulating natural killer (NK) cells and tissue resident helper-like ILC1 (ILC1), which are considered less cytotoxic than their NK-cell counterparts 4 .Notably, ILC1 accumulate in the inflamed intestines of Inflammatory Bowel Disease (IBD) patients 5 , however the nature of their subset-specific interactions with the epithelium has remained elusive. Understanding the impact of ILC1 enrichment could offer novel avenues for treating this complex disease, which is a pressing issue as only a third of patients respond to gold standard TNFα-blocking biologics 6 .Teasing apart the role of rare cell populations in multifactorial diseases is challenging, and redundant cytokine signalling pathways in vivo can obscure ILC-specific phenotypes. Thus, to explore the impact of ILC1 on IEC we developed a reductionist co-culture system with murine small intestine organoids (SIO) 7 . We unexpectedly found that ILC1-derived TGFβ1 induces p38γ activity to drive epithelial Cd44v6 expression and SIO proliferation. Pathway analysis of co-culture transcriptomes also predicted ILC1-driven matrisome remodelling, so we developed highly defined PEG-based hydrogels to quantitatively characterize the impact of ILC1 on matrix remodelling in a human iPSC-derived organoid model (HIO) 8 . We not only confirmed that IBD patient-derived ILC1 express TGFB1 and upregulate CD44v6, but also that they p...

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Interleukin-2 induces the in vitro maturation of human pluripotent stem cell-derived intestinal organoids

Cited by 92 publications

References 50 publications

Interleukin‐2 induces extracellular matrix synthesis and TGF‐β2 expression in retinal pigment epithelial cells

Interleukin‐2 induces extracellular matrix synthesis and TGF‐β2 expression in retinal pigment epithelial cells

Gastrointestinal tract modeling using organoids engineered with cellular and microbiota niches

ILC1-derived TGFβ1 drives intestinal remodelling

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