Schlafen 3 induction by cyclic strain regulates intestinal epithelial differentiation

Area of Science:

• Gastroenterology
• Cell Biology
• Molecular Biology

Background:

• The intestinal epithelium undergoes mechanical deformation during normal gut function.
• In vitro studies show cyclic strain enhances intestinal epithelial proliferation and an absorptive phenotype, marked by increased dipeptidyl dipeptidase (DPPIV) expression.
• Schlafen 3 is a newly identified gene linked to cellular differentiation.

Purpose of the Study:

• To investigate if Schlafen 3 mediates the effects of cyclic strain on intestinal epithelial cell (IEC)-6 differentiation.
• To determine the role of Schlafen 3 in strain-induced DPPIV activity and overall intestinal epithelial differentiation.

Main Methods:

• Rat IEC-6 cells cultured on collagen were subjected to cyclic strain.
• Schlafen 3 expression was modulated using small interfering RNA (siRNA).
• DPPIV activity, cell proliferation, and signaling pathways (Src, PI3-kinase, p38, ERK) were analyzed.

Main Results:

• Cyclic strain increased Schlafen 3 mRNA and protein levels.
• Schlafen 3 knockdown reduced basal DPPIV activity and abolished strain-induced DPPIV stimulation.
• Schlafen 3 reduction also inhibited DPPIV induction by sodium butyrate and TGF-beta but not proliferation induced by strain or EGF.
• Strain induction of Schlafen 3 involved Src, PI3-kinase, and p38 activation.

Conclusions:

• Cyclic strain induces an absorptive phenotype in rat IEC-6 cells via Src-, p38-, and PI3-kinase-dependent induction of Schlafen 3.
• Schlafen 3 is a key mediator of strain-induced DPPIV activity and plays a significant role in intestinal epithelial differentiation.
• Schlafen 3 or its human homologs may be important for maintaining gut mucosa function.