Intestinal epithelial plasticity and regeneration via cell dedifferentiation

The intestinal epithelium possesses a great capacity of self-renewal under normal homeostatic conditions and of regeneration upon damages. The renewal and regenerative processes are driven by intestinal stem cells (ISCs), which reside at the base of crypts and are marked by Lgr5. As Lgr5⁺ ISCs undergo fast cycling and are vulnerable to damages, there must be other types of cells that can replenish the lost Lgr5⁺ ISCs and then regenerate the damage epithelium. In addition to Lgr5⁺ ISCs, quiescent ISCs at the + 4 position in the crypt have been proposed to convert to Lgr5⁺ ISCs during regeneration. However, this "reserve stem cell" model still remains controversial. Different from the traditional view of a hierarchical organization of the intestinal epithelium, recent works support the dynamic "dedifferentiation" model, in which various cell types within the epithelium can de-differentiate to revert to the stem cell state and then regenerate the epithelium upon tissue injury. Here, we provide an overview of the cell identity and features of two distinct models and discuss the possible mechanisms underlying the intestinal epithelial plasticity.