The intestinal stem cell

Abstract

The epithelium of the adult mammalian intestine is in a constant dialog with its underlying mesenchyme to direct progenitor proliferation, lineage commitment, terminal differentiation, and, ultimately, cell death. The epithelium is shaped into spatially distinct compartments that are dedicated to each of these events. While the intestinal epithelium represents the most vigorously renewing adult tissue in mammals, the stem cells that fuel this self-renewal process have been identified only recently. The unique epithelial anatomy makes the intestinal crypt one of the most accessible models for the study of adult stem cell biology. This review attempts to provide a comprehensive overview of four decades of research on crypt stem cells.

Figure 1.

The exact identity of the intestinal stem cells has proven controversial over the last 30 years, with two opposing models dominating the literature. (Top panel) In the“+4 position”model proposed in the late 1950s, it was assumed that that the crypt base is exclusively populated by terminally differentiated Paneth Cells and the stem cells must therefore be located just above the Paneth cells at the +4 position. This model, largely championed by Chris Potten and colleagues (Marshman et al. 2002) predicts that the enterocytes, goblet cells, and enteroendocrine cells are derived from +4 cell progeny that differentiate as they migrate out of the crypts onto the villi. In contrast, the Paneth cells differentiate as they migrate down from the +4 position toward the crypt base. (Bottom panel) A more recent, but less well accepted model, the “stem cell zone” model proposed by Leblond and colleagues in the early 1970s (Cheng and Leblond 1974a, b) states that small, undifferentiated, cycling cells (termed crypt base columnar cells) intermingled with the Paneth cells are likely to be the true intestinal stem cells. Definitive proof for either model has proven elusive due to the lack of specific markers for these cells

Figure 2.

(Left panel) Lgr5 is predicted to encode a 7-transmembrane protein with a large extracellular domain for ligand binding and a short cytoplasmic tail for coupling to G-proteins. (Middle panel) The Lgr5 protein is exclusively expressed on the Crypt-Base-Columnar (CBC) cells interspersed between the Paneth cells at the base of the intestinal crypts (visualized here by confocal microscopy for EGFP fluorescence in crypts from the Lgr5-EGFP KI mouse). (Right panel) The Lgr5^+ve CBC cells are actively cycling, with the entire population staining positive for BrdU after 24 h of continuous labeling.

Figure 3.

Whole-mount photograph of small intestine (top series) and colon (bottom series) from Lgr5-EGFP-IresCreERT2/Rosa26-LacZ mice induced 6 mo previously with low-dose Tamoxifen. Villi containing ribbons of blue cells originating from the Lgr5^+ve CBC cells are readily visible in the small intestine. (Top right panel) The various cell-types of the villus epithelium are all present within each of these blue ribbons, proving that the Lgr5^+ve CBC cells are multipotent as well as being long-lived. (Bottom rightpanel) Similar observations are made in the colon, demonstrating that the Lgr5^+ve cells are the stem cells of both the small intestine and colon.