Most cell types are polarized with distinct structural orientations or protein localization patterns that allow cells to perform context-dependent functions in space and time in response to physiological regulation (Forte and Yao, 1996). Epithelial cell polarity is characterized by cells with apical and basolateral membrane domains, and the establishment and maintenance of cell polarity are crucial during development to specify cell fate and functions, e.g. epithelial cells undergo dynamic renewal to orchestrate the tissue homeostasis in gastrointestinal tracts for digestive physiology (Yao and Forte, 2003). However, the molecular mechanisms underlying the dynamic lineage specification and heterogenetic cell fate decision in epithelial tissues have remained elusive until the identification of leucine-rich repeat-containing, G-protein-coupled receptor 5 (Lgr5) epithelial stem cells (Sato et al., 2009). Since then, Clevers and colleagues have made paradigm shift discoveries in epithelial cell linage specification and fate determination using the mini-gut epithelial organoids comprising Lgr5+ stem cells and all types of differentiated lineages (Sato et al., 2009; Barker et al., 2010).