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Characterization of molecular signatures of intestinal epithelial cells in a mouse model of colitis.

如澤, 浩樹 東京大学 DOI:10.15083/0002004338

2022.06.22

概要

【Introduction】
Inflammatory bowel diseases (IBDs) including ulcerative colitis (UC) and Crohn’s disease (CD) are characterized by chronic inflammation involving intestinal tissue damage. Although their etiology remains unclear, recent studies indicate that intestinal epithelial cells (IECs) forming the mucosal surface of the intestine, which governs interactions between the luminal microbiota and the underlying lamina propria, play a key role in IBD pathogenesis. For example, a recent study has shown that transcriptional signatures for IECs from patients with IBD were significantly altered compared to those from non-IBD controls. Interestingly, genes that were upregulated in the IECs of IBD patients included pro-inflammatory mediators. Moreover, these transcriptional alterations were maintained in the intestinal epithelial stem cell (IESC) compartment. These findings support the hypothesis that IESCs are altered to a pro-inflammatory mediator secreting phenotype and contribute to the development of chronic inflammation, the pathology of human IBD. Furthermore, IBD increases the risk of developing colitis-associated cancer (CAC), suggesting the involvement of altered IESCs in the development of CAC. In this study, I analyzed the transcriptional alterations in IESCs during colitis using organoid culture technology enabling the maintenance of IESCs in vitro and investigated the molecular mechanism that induces the transcriptional alterations in IESCs along with the influence of IESC alteration on the pathogenesis of colitis and CAC in mice.

【Results and discussion】
First, to analyze the transcriptional alterations in IESCs during colitis, I established several organoids from IESCs of untreated mice (control organoids) and DSS-treated mice, a model of colitis (DSS organoids) (Figure 1A). Then, I performed DNA microarray analysis of the control and DSS organoids. Many genes were found to be differentially expressed (Figure 1B). In particular, pro-inflammatory mediators including Saa3 and Lrg1 were highly upregulated in DSS organoids compared to those in control organoids (Figure 1C). To identify the genes responsible for the induction of these pro- inflammatory mediators, I compared the transcriptional profiles and found that the transcription factor C/EBPδ is highly upregulated in the DSS organoids compared to that in control organoids. Gene knockdown and forced expression in organoids demonstrated that C/EBPδ is responsible for the induction of several pro-inflammatory mediators(Figure 2). These results suggest that C/EBPδ may contribute to the enhancement of colitis through induction of pro-inflammatory mediators in IESCs.
To verify this possibility, I treated WT and C/EBPδ KO mice with 2.5% DSS and examined their colitis susceptibility by monitoring the loss of body weight, which indicates intestinal tissue damage and inflammation. I found that DSS-treated WT and C/EBPδ KO mice were similarly affected by the DSS administration. However, body weight recovery after withdrawal of DSS was significantly promoted in C/EBPδ KO mice with a reduced number of infiltrated leukocytes including monocytes and eosinophils, which are essential for DSS-colitis (Figure 3). These findings suggest that C/EBPδ is important for delaying recovery from DSS-induced colitis, likely by prolongation of inflammatory response. Furthermore, transcriptional profiling of organoids isolated from DSS- treated WT and C/EBP δ KO mice demonstrated that transcriptional induction of pro-inflammatory mediators including Saa3 and Lrg1 was dependent on C/EBPδ at least in organoids. Together these results support a key function of C/EBPδ in the alteration of IESCs to a pro-inflammatory mediator-secretory phenotype during DSS-colitis. Furthermore, I found that the number of colorectal tumors in AOM/DSS-treated C/EBPδ KO mice was significantly reduced compared to that in wild type mice, accompanied by a reduction in expression of pro-inflammatory mediators in tumor cells. These findings support the hypothesis that IESCs that are reprogrammed
to the pro-inflammatory mediator- secretory phenotype in a C/EBPδ- dependent manner prolong intestinal inflammation and promote CAC development in mice (Figure 4).

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