An essential mesenchymal function for miR-143/145 in intestinal epithelial regeneration

Area of Science:

• Molecular Biology
• Gastroenterology
• Oncology

Background:

• The miR-143/145 microRNA (miRNA) cluster is frequently downregulated in colon cancer.
• Overexpression of miR-143/145 inhibits tumorigenesis, suggesting a tumor suppressor role.
• Previous studies indicated a cell-autonomous function for these miRNAs in epithelial tissues.

Purpose of the Study:

• To investigate the in vivo function of the miR-143/145 cluster in intestinal physiology and disease.
• To determine the cellular compartment responsible for miR-143/145 function in the intestine.
• To elucidate the mechanism by which miR-143/145 influences epithelial regeneration and tumorigenesis.

Main Methods:

• Generation of mice with targeted deletion of the miR-143/145 miRNA cluster.
• Assessment of intestinal development and epithelial regeneration after injury in knockout mice.
• Analysis of miRNA expression patterns and target gene regulation within different intestinal compartments.
• Investigation of smooth muscle and myofibroblast function and their impact on epithelial repair.

Main Results:

• Intestinal development was normal in miR-143/145-deficient mice.
• Epithelial regeneration after injury was significantly impaired in the absence of miR-143/145.
• miR-143/145 are expressed and function exclusively in the mesenchymal compartment (smooth muscle and myofibroblasts).
• Impaired regeneration resulted from smooth muscle and myofibroblast dysfunction, linked to derepression of the target gene Igfbp5 and altered IGF signaling.

Conclusions:

• miR-143/145 are essential for intestinal epithelial wound healing, acting via mesenchymal cells.
• These findings challenge the established view of miR-143/145 as cell-autonomous epithelial tumor suppressors in colon cancer.
• The study highlights the critical role of mesenchymal-epithelial interactions in regulating intestinal repair.