Intestinal stem cells and celiac disease

Abstract

Stem cells (SCs) are the key to tissue genesis and regeneration. Given their central role in homeostasis, dysfunctions of the SC compartment play a pivotal role in the development of cancers, degenerative disorders, chronic inflammatory pathologies and organ failure. The gastrointestinal tract is constantly exposed to harsh mechanical and chemical conditions and most of the epithelial cells are replaced every 3 to 5 d. According to the so-called Unitarian hypothesis, this renewal is driven by a common intestinal stem cell (ISC) residing within the crypt base at the origin of the crypt-to-villus hierarchical migratory pattern. Celiac disease (CD) can be defined as a chronic immune-mediated disease that is triggered and maintained by dietary proteins (gluten) in genetically predisposed individuals. Many advances have been achieved over the last years in understanding of the pathogenic interactions among genetic, immunological and environmental factors in CD, with a particular emphasis on intestinal barrier and gut microbiota. Conversely, little is known about ISC modulation and deregulation in active celiac disease and upon a gluten-free diet. Nonetheless, bone marrow-derived SC transplantation has become an option for celiac patients with complicated or refractory disease. This manuscript summarizes the "state of the art" regarding CD and ISCs, their niche and potential role in the development and treatment of the disease.

Keywords: CD133; Celiac disease; Gut barrier; Gut microbiota; Intestinal stem cells; Lgr5; Paneth cells.

Figure 1

Schematic representation of the crypt/villus axis. Putative intestinal stem cells (ISCs) reside either at the crypt base, between Paneth cells, as Crypt Base Columnar Cells (CBCs), or in position +4 from the bottom of the crypt, as Label Retaining Cells (LRCs). ISCs give rise to Transit Amplifying (TA) cells that are able to migrate upwards and progressively maturate losing their proliferative capability to become fully-differentiated villous epithelial cells.

Figure 2

Lineage specification of intestinal stem cells. Intestinal stem cells (ISCs)-Crypt Columnar Cells (CBCs) and Label Retaining Cells (LRCs)-can divide asymmetrically or symmetrically to maintain the stem cell compartment. ISCs give rise to Transit Amplifying (TA) cells which actively proliferate and can further differentiate into enterocytes, tuft cells, enteroendocrine (EE) cells or goblet cells. Wnt signaling maintains the stem-like phenotype of ISCs, while Notch signaling maintains the proliferation of progenitor cells. In the upper crypt region, hedgehog (hh) triggers BMP expression in stromal cells which activates PTEN expression; all these factors inhibit Wnt signaling in the ISC niche.

Figure 3

Causative factors in celiac disease. The pathogenesis of celiac disease involves: (1) host genetic background (HLA-DQ2 or DQ8 and other non-HLA genes); (2) an external trigger (gluten); and (3) environmental cofactors (such as intestinal pathogens, altered gut microbiota composition, infant-feeding practices and some immune-modulatory drugs).