Under constant barrage from chemical, pathogenic, and mechanical stresses, the intestinal epithelium is homeostatically replenished by a pool of Lgr5⁺ intestinal stem cells (ISCs), residing at the bottom of submucosal invaginations termed crypts. Decorated with the RSPO-receptor LGR5, which potentiates canonical Wnt/β-catenin signalling, these actively cycling cells can both self-renew and give rise to short-lived transit-amplifying cells. In turn, transit-amplifying cells undergo successive rounds of cell division and differentiation to generate the full gamut of terminally differentiated intestinal cell types tasked with performing pleiotropic absorptive, secretory, immune, and barrier functions. The self-renewal capabilities and multipotency of Lgr5⁺ ISCs are tightly controlled by instructive cues emanating from epithelial and stromal components of the ISC niche in the vicinity of the lower crypt. 

The intestinal epithelium displays a remarkable ability to regenerate following demise of homeostatic Lgr5⁺ ISCs post injury. Plasticity—the ability of lineage-restricted cells to regain self-renewal capacity and multi-lineage differentiation potential in response to environmental cues—is pervasive among multiple intestinal cell populations. Reserve stem-like cells, lineage-committed progenitors, and/or fully differentiated cell types can all contribute to regeneration and repair through dedifferentiation and reversion to an Lgr5⁺ stem-like state. In line with the pervasive plasticity of the intestinal epithelium, accumulating evidence supports both “bottom-up” and “top-down” histogenesis of colorectal tumours whereby the cells-of-origin comprise either ISCs at the crypt base or differentiated cells at the crypt apex, respectively.