Somatic inflammatory gene mutations in human ulcerative colitis epithelium

Nanki, Kosaku; Fujii, Masayuki; Shimokawa, Mariko; Matano, Mami; Nishikori, Shingo; Date, Shoichi; Takano, Ai; Toshimitsu, Kohta; Ohta, Yuki; Takahashi, Sirirat; Sugimoto, Seiichiro; Ishimaru, Kazuhiro; Kawasaki, Kenta; Nagai, Yoko; Ishii, Ryota; Yoshida, Kosuke; Sasaki, Nobuo; Hibi, Toshifumi; Ishihara, Soichiro; Kanai, Takanori; Sato, Toshiro

doi:10.1038/s41586-019-1844-5

Cited by 205 publications

(158 citation statements)

References 52 publications

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“…Various efforts have been made to overcome these challenges by increasing the number of experimental replicates, testing multiple lines, and validating the effect of different passage numbers to improve experimental statistics. Interestingly, organoids grown in a dome-shaped Matrigel scaffold have shown heterogeneity in size and shape, which has been reportedly observed in previous studies ( Kassis et al., 2019 ; Nanki et al., 2020 ). Yet, the underlying mechanism of this intra-heterogeneity in a Matrigel dome is unclear.…”

Section: Introductionsupporting

confidence: 71%

Spatiotemporal Gradient and Instability of Wnt Induce Heterogeneous Growth and Differentiation of Human Intestinal Organoids

Shin

Min

et al. 2020

iScience

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Summary In a conventional culture of three-dimensional human intestinal organoids, extracellular matrix hydrogel has been used to provide a physical space for the growth and morphogenesis of organoids in the presence of exogenous morphogens such as Wnt3a. We found that organoids embedded in a dome-shaped hydrogel show significant size heterogeneity in different locations inside the hydrogel. Computational simulations revealed that the instability and diffusion limitation of Wnt3a constitutively generate a concentration gradient inside the hydrogel. The location-dependent heterogeneity of organoids in a hydrogel dome substantially perturbed the transcriptome profile associated with epithelial functions, cytodifferentiation including mucin 2 expression, and morphological characteristics. This heterogeneous phenotype was significantly mitigated when the Wnt3a was frequently replenished in the culture medium. Our finding suggests that the morphological, transcriptional, translational, and functional heterogeneity in conventional organoid cultures may lead to a false interpretation of the experimental results in organoid-based studies.

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Section: Introductionsupporting

confidence: 71%

Spatiotemporal Gradient and Instability of Wnt Induce Heterogeneous Growth and Differentiation of Human Intestinal Organoids

Shin

Min

et al. 2020

iScience

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“…This study also suggests that skin inflammation such as that induced by mut-CARD14 may promote BIR. Recent studies on patients with ulcerative colitis have revealed that human intestinal stem cells exposed to long-standing inflammation adapt to such inflammation by acquiring genetic and genomic alterations including LOH, associated with the downregulation of IL-17 signalling 11,12 . Furthermore, long-tract LOH is frequently seen in skin lesions of porokeratosis, a common autoinflammatory keratinisation disease 41 .…”

Section: Discussionmentioning

confidence: 99%

Curing genetic skin disease through altered replication stress response

Miyauchi¹,

Suzuki²,

Takeda³

et al. 2020

Preprint

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Revertant mosaicism, or "natural gene therapy", refers to the spontaneous in vivo reversion of an inherited mutation in a somatic cell. Only ~50 human genetic disorders exhibit revertant mosaicism, implicating a distinctive role played by mutant proteins in somatic correction of a pathogenic germline mutation. However, the process by which mutant proteins induce somatic genetic reversion in these diseases remains unknown. Here we show that heterozygous pathogenic CARD14 mutations causing autoinflammatory skin diseases, including psoriasis and pityriasis rubra pilaris, are repaired mainly via homologous recombination. Rather than altering the DNA damage response to exogenous stimuli such as X-irradiation or etoposide treatment, mutant CARD14 increased DNA double-strand breaks under conditions of replication stress. Furthermore, mutant CARD14 suppressed new origin firings without promoting crossover events in the replication stress state. Together, these results suggest that mutant CARD14 alters the replication stress response and preferentially drives break-induced replication (BIR), which is generally suppressed in eukaryotes. Our results highlight the involvement of BIR in reversion events, thus revealing a previously undescribed role of BIR that could potentially be exploited to develop therapeutics for currently intractable genetic diseases.

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“… 99 A recent study comparing epithelial organoids derived from 71 patients, 16 without colitis, 29 with colitis lacking dysplasia, and 26 from patients with colitis-associated cancer, showed mutations in the IL-17 signaling pathway that confer resistance to an IL-17A-induced apoptotic response. 100 Like novel chemotherapeutic testing for cancer, ulcerative colitis and normal colonic organoids can be treated with cytokines and bacterial components to recapitulate the colitis phenotype, and then treated with novel agents to assess suppression of the immune response and regeneration of normal crypts. 101 – 103 One of these studies showed that naltrexone alleviated endoplasmic reticulum stress in organoids of patients with IBD after treatment with inflammatory stimuli.…”

Section: Methodsmentioning

confidence: 99%