Intestinal stem cells and their roles during mucosal injury and repair

Abstract

The ability of the host to respond to intestinal injury requires the regeneration of native tissue through a highly orchestrated response from the intestinal stem cells, a population of cells located within the intestinal crypts that have the capability to repopulate the entire villous. The field of intestinal stem cell biology is thus of great interest to surgeons and non-surgeons alike, given its relevance to diseases of intestinal injury and inflammation such as inflammatory bowel disease, trauma, and necrotizing enterocolitis. The field of intestinal stem cell research has been advanced recently by the identification of the putative marker, Lgr5, which has allowed for the isolation and further characterization of the intestinal stem cell. Under the control of the WNT signaling pathway, Lgr5 marks the rapidly dividing cells of the intestinal crypt, and identifies a population of cells that is capable of regenerating the entire villous. We now review the identification of Lgr5 as an intestinal stem cell marker, identify controversies in the intestinal stem cell field, and highlight the response of the intestinal stem cell to injury within the intestinal mucosa that may occur clinically.

Figure 1. Frequency of literature citations for intestinal stem cells over 15 years

A literature search was performed on PubMed for “intestinal stem cell,” which revealed 93 publications. With limitations of English language and a timeline of the last 15 years, three publications were excluded and the years of publication of the remaining 90 were charted, demonstrating a significant increase over the past five years.

Figure 2. Schematic of the intestinal stem cell compartment and WNT signaling

Panel A: Crypt based columnar (CBC) cells residing in interspersed between Paneth cells in the intestinal crypt express the putative stem cell marker Lgr5 and represent actively dividing cells. Cell located in the +4 position are referred to as label-retaining cells (LRC) and are thought to represent quiescent stem cells. The proliferative zone superior to these is populated by transient amplifying cells (TACs), which further differentiate into absorptive, goblet, enteroendocrine, and Paneth cells. Panel B: WNT proteins bind to the cell surface receptor Frizzled in addition to the transmembrane receptor LRP. This binding event activates Dishevelled (DSH) family proteins, and this complex is responsible for the inhibition of a second complex of proteins includes axin, GSK-3, and the protein APC. The axin/GSK-3/APC complex controls degradation of β-catenin. After the degradation complex is inhibited, stabilized, free cytoplasmic β-catenin is able to enter the nucleus and interact with TCF transcription factors to promote specific gene expression, such as Lgr5.

Figure 2. Schematic of the intestinal stem cell compartment and WNT signaling

Panel A: Crypt based columnar (CBC) cells residing in interspersed between Paneth cells in the intestinal crypt express the putative stem cell marker Lgr5 and represent actively dividing cells. Cell located in the +4 position are referred to as label-retaining cells (LRC) and are thought to represent quiescent stem cells. The proliferative zone superior to these is populated by transient amplifying cells (TACs), which further differentiate into absorptive, goblet, enteroendocrine, and Paneth cells. Panel B: WNT proteins bind to the cell surface receptor Frizzled in addition to the transmembrane receptor LRP. This binding event activates Dishevelled (DSH) family proteins, and this complex is responsible for the inhibition of a second complex of proteins includes axin, GSK-3, and the protein APC. The axin/GSK-3/APC complex controls degradation of β-catenin. After the degradation complex is inhibited, stabilized, free cytoplasmic β-catenin is able to enter the nucleus and interact with TCF transcription factors to promote specific gene expression, such as Lgr5.