Colonic crypt stem cell functions are controlled by tight junction protein claudin‐7 through Notch/Hippo signaling

Abstract

The tight junction protein claudin‐7 is essential for tight junction function and intestinal homeostasis. Cldn7 deletion in mice leads to an inflammatory bowel disease‐like phenotype exhibiting severe intestinal epithelial damage, weight loss, inflammation, mucosal ulcerations, and epithelial hyperplasia. Claudin‐7 has also been shown to be involved in cancer metastasis and invasion. Here, we test our hypothesis that claudin‐7 plays an important role in regulating colonic intestinal stem cell function. Conditional knockout of Cldn7 in the colon led to impaired epithelial cell differentiation, hyperproliferative epithelium, a decrease in active stem cells, and dramatically altered gene expression profiles. In 3D colonoid culture, claudin‐7–deficient crypts were unable to survive and form spheroids, emphasizing the importance of claudin‐7 in stem cell survival. Inhibition of the Hippo pathway or activation of Notch signaling partially rescued the defective stem cell behavior. Concurrent Notch activation and Hippo inhibition resulted in restored colonoid survival, growth, and differentiation to the level comparable to those of wild‐type derived crypts. In this study, we highlight the essential role of claudin‐7 in regulating Notch and Hippo signaling–dependent colonic stem cell functions, including survival, self‐renewal, and differentiation. These new findings may shed light on potential avenues to explore for drug development in colorectal cancer.

Exploring Importance and Regulation of Autophagy in Cancer Stem Cells and Stem Cell-Based Therapies

“…Further study specifically designed to examine the impact of PDCD4 inhibition on CSCs is necessary to offer a conclusive response. This could involve carrying out research utilizing particular markers and assays that are exclusive to CSCs in order to differentiate the impact on CSCs from that of the overall tumor population [ 67 ]. Mitophagy, a selective autophagy process targeting mitochondria, is crucial for maintaining mitochondrial quality and homeostasis by removing damaged or dysfunctional mitochondria.…”