Abstract
Inflammation often induces regeneration to repair the tissue damage. However, chronic inflammation can transform temporary hyperplasia into a fertile ground for tumorigenesis. Here, we demonstrate that the microRNA miR-34a acts as a central safeguard to protect the inflammatory stem cell niche and reparative regeneration. Although playing little role in regular homeostasis, miR-34a deficiency leads to colon tumorigenesis after Citrobacter rodentium infection. miR-34a targets both immune and epithelial cells to restrain inflammation-induced stem cell proliferation. miR-34a targets Interleukin six receptor (IL-6R) and Interleukin 23 receptor (IL-23R) to suppress T helper 17 (Th17) cell differentiation and expansion, targets chemokine CCL22 to hinder Th17 cell recruitment to the colon epithelium, and targets an orphan receptor Interleukin 17 receptor D (IL-17RD) to inhibit IL-17-induced stem cell proliferation. Our study highlights the importance of microRNAs in protecting the stem cell niche during inflammation despite their lack of function in regular tissue homeostasis.
Highlights
The colon epithelium is constantly regenerated by stem cells residing at the bottoms of the intestinal crypts (Humphries and Wright, 2008)
Infection of pathogenic bacteria in the colon can disrupt the normal gut microbiome and cause chronic inflammation, which has been linked to diseases including as inflammatory bowel disease (IBD) and recognized as a significant risk factor for colorectal cancer (CRC) development (Gagniere et al, 2016; Wang and Karin, 2015; Collins et al, 2011)
We demonstrate that miR-34a acts as safeguard to protect the stem cell niche during inflammation-induced reparative regeneration. miR-34a deficiency led to colon tumorigenesis after C. rodentium infection, where T helper 17 (Th17) cell infiltration and epithelial stem cell proliferation were observed
Summary
The colon epithelium is constantly regenerated by stem cells residing at the bottoms of the intestinal crypts (Humphries and Wright, 2008). Infection of pathogenic bacteria in the colon can disrupt the normal gut microbiome and cause chronic inflammation, which has been linked to diseases including as inflammatory bowel disease (IBD) and recognized as a significant risk factor for colorectal cancer (CRC) development (Gagniere et al, 2016; Wang and Karin, 2015; Collins et al, 2011). It has been estimated that chronic inflammation and persistent infections contribute to a significant portion of human cancers, especially CRC (Wang and Karin, 2015; Zur Hausen, 2009). Inflammation is associated with damage to the tissue; on the other hand, it triggers stem cell proliferation and reparative regeneration (Karin and Clevers, 2016). Events of damage and inflammation have been associated with regenerative signaling pathways such as Wnt to increase the number of stem cells and cause
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