Hierarchy and Plasticity in the Intestinal Stem Cell Compartment

Abstract

Somatic stem cells maintain tissue homeostasis by organizing themselves in such a way that they can maintain proliferative output while simultaneously protecting themselves from DNA damage that may lead to oncogenic transformation. There is considerable debate about how such stem cell compartments are organized. Burgeoning evidence from the small intestine and colon provides support for a two-stem cell model involving an actively proliferating but injury-sensitive stem cell and a rare, injury-resistant pool of quiescent stem cells. Parallel with this evidence, recent studies have revealed considerable plasticity within the intestinal stem cell (ISC) compartment. We discuss the evidence for plasticity and hierarchy within the ISC compartment and how these properties govern tissue regeneration and contribute to oncogenic transformation leading to colorectal cancers.

Figure 1

Intestinal stem cell fate determination under basal conditions. In the resting state, reserve ISCs (blue) periodically divide to give rise to the active crypt base columnar stem cells (CBCs, green). These active CBCs then either produce transit-amplify progeny (T/A cells, dark grey), which go on to divide very rapidly in order to produce large quantities of enterocytes (light grey), or can generate secretory progenitor cells (maroon). These secretory progenitor cells then commit to Paneth, goblet, or enteroendocrine cell lineages (yellow, navy blue, or purple, respectively).

Figure 2

Intestinal regeneration after injury. Exposure to DNA damaging agents such as high-dose gamma radiation or chemotherapeutics ablates actively cycling cells, including CBCs and transit-amplifying cells. Some cells are able to survive DNA damage, and some of these cells can contribute to the post-injury regenerative process. In response to DNA damage, reserve ISCs enter the cell cycle to replenish the CBC compartment and epithelium. Additionally, some reports indicate that Wnt^Low CBCs above the crypt base as well as cells downstream of the CBC can resist DNA damage-induced cell death and contribute to repopulation, including a rare subpopulation of secretory progenitor cells. Further, in non-physiological injury settings in which CBCs are genetically ablated with diphtheria toxin (asterisk), transit-amplifying cells marked by Alpi-CreER can fall back into the CBC niche and re-establish stem cell identity. The quantitative contribution of secretory progenitors and Alpi-CreER-marked cells to regeneration based on lineage tracing is, however, minimal, and no evidence exists demonstrating its functional importance.

Figure 3

Model of intestinal stem cell compartment organization. In the hierarchical model, a population of rare stem cells that lack canonical Wnt pathway activity and reside in the quiescent G0 state sits atop the hierarchy. During homeostasis, these cells periodically divide to generate CBCs driven by high Wnt pathway activity and marked by Lgr5 expression. Whether CBCs can re-enter the Wnt^Negative reserve ISC state remains an outstanding question. CBCs divide symmetrically and stochastically give rise to transit-amplifying cells which begin to lose developmental potency as they undergo the massive proliferation required to generate large numbers of short-lived enterocytes. Conversely, CBCs can activate Dll1 expression and commit to the secretory lineage. These secretory progenitor cells retain some developmental potency, even after they exit the cell cycle and retain DNA label while they acquire hallmarks of enteroendocrine and Paneth cell lineages. The secretory progenitor cells can also give rise to goblet cells, a fate decision that is presumably coupled to additional cell divisions as no evidence for goblet cell identity is found in the short-term label retaining cell population. Long-term label retaining cells are terminally differentiated Paneth cells that have lost developmental potency.