The Endo-lysosomal system: A Key Player in Intestinal Stem Cell Function and Gut Health

Abstract

Intestinal stem cells (ISCs) are essential for maintaining the health and homeostasis of the intestinal epithelium through their self-renewal and differentiation capacities. Understanding the molecular and cellular regulation mechanisms behind ISC function will prove to be useful for understanding intestinal homeostasis in health and disease. The endo-lysosomal system plays a central role in regulating ISC identity and function through processes such as vesicular cargo trafficking, degradation, nutrient sensing, and autophagy. Amplification or attenuation of the signaling of several stem cell niche factors happens through endo-lysosomal trafficking and degradation, influencing ISC proliferation and differentiation rates. Nutrient sensing and signaling through lysosome positioned mTOR pathways, impacts ISC self-renewal, while autophagy supports ISC survival, stress resistance, and tissue repair. Dysregulation or excessive activation of these processes can lead to aberrant proliferation, differentiation, and diseases such as inflammatory bowel disease and cancer. Despite its importance, the specific contributions of the endo-lysosomal system to ISC identity and function remain largely underexplored. Emerging technologies, like organoid models, advanced imaging, and single-cell sequencing, will improve our understanding of these regulatory mechanisms. Further insights into the endo-lysosomal regulation of ISCs could offer promising therapeutic developments to ultimately improve intestinal health in metabolic and inflammatory disorders as well as in cancer.