Intestinal Stem Cells and Their Roles During Mucosal Injury and Repair

Department of Surgery, Division of Pediatric Surgery, Children's Hospital of Pittsburgh of UPMC and the University of Pittsburgh, Pittsburgh, Pennsylvania 15224, USA.
Journal of Surgical Research (Impact Factor: 1.94). 05/2011; 167(1):1-8. DOI: 10.1016/j.jss.2010.04.037
Source: PubMed


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.

Download full-text


Available from: Chhinder P Sodhi
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: qué algunos animales tienen gran capacidad regenerativa y otros no, es una pregunta que ha sido investigada a fondo por muchos años y aunque actualmente aún no se tiene respuesta, este conoci-miento ha sentado las bases de la medicina regenerativa para su aplicación en tratamientos de enfermedades crónico-degenerativas o bien de amputaciones de extremidades en humanos. INTRODUCCIÓN ¿Qué es la regeneración? El término regeneración se ha usado ampliamente para explicar los fenómenos de reemplazo homeostático de los tejidos, por ejemplo: la piel, el linaje sanguí-neo y el epitelio intestinal. Muchos organismos, a lo largo de su vida, pierden constantemente partes de su cuerpo y tienen la capacidad de reemplazarlos. Por ejemplo, en la planaria y en los gusanos anélidos existe una alta capacidad para regenerar todo su cuerpo. En vertebrados, algunos anfibios tienen la capa-cidad de reemplazar extremidades y colas, mientras que especies como el pez cebra regeneran el corazón. Los venados, recambian periódicamente sus astas. Los mamíferos, incluido el humano, son capaces de reparar el tejido muscular esquelético dañado o el tejido hepático; en las hembras, tras su período mens-trual se lleva a cabo la renovación del endometrio.
    Full-text · Chapter · Jan 2011
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Factors regulating the proliferation and apoptosis of intestinal stem cells (ISC's) remain incompletely understood. Because ISC's exist among microbial ligands, immune receptors such as toll-like receptor-4 (TLR4) could play a role. We now hypothesize that ISCs express TLR4, and that the activation of TLR4 directly on the intestinal stem cells regulates their ability to proliferate or to undergo apoptosis. Using flow cytometry and fluorescent in situ hybridization for the intestinal stem cell marker Lgr5 we demonstrate that TLR4 is expressed on the Lgr5-positive intestinal stem cells. TLR4 activation reduced proliferation and increased apoptosis in ISC's both in vivo and in ISC-organoids, a finding not observed in mice lacking TLR4 in the Lgr5-positive ISCs, confirming the in vivo significance of this effect. To define molecular mechanisms involved, TLR4 inhibited ISC proliferation and increased apoptosis via the p53-upregulated modulator of apoptosis (PUMA), as TLR4 did not affect crypt proliferation or apoptosis in organoids or mice lacking PUMA. In vivo effects of TLR4 on ISCs required TIR-domain-containing adapter-inducing interferon(TRIF), but were independent of myeloid-differentiation primary response-gene(88) (MYD88) and TNF. Physiological relevance was suggested as TLR4 activation in necrotizing enterocolitis (NEC) led to reduced proliferation and increased apoptosis of the intestinal crypts in a manner that could be reversed by inhibition of PUMA, both globally or restricted to the intestinal epithelium. These findings illustrate that TLR4 is expressed on ISCs where it regulates their proliferation and apoptosis through activation of PUMA, and that TLR4 regulation of ISCs contributes to the pathogenesis of NEC.
    Full-text · Article · Sep 2012 · Journal of Biological Chemistry
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Abstract Chronic exposure to high concentrations of hexavalent chromium (Cr(VI)) in drinking water causes intestinal adenomas and carcinomas in mice, but not in rats. Cr(VI) causes damage to intestinal villi and crypt hyperplasia in mice after only one week of exposure. After two years of exposure, intestinal damage and crypt hyperplasia are evident in mice (but not rats), as are intestinal tumors. Although Cr(VI) has genotoxic properties, these findings suggest that intestinal tumors in mice arise as a result of chronic mucosal injury. To better understand the mode of action (MOA) of Cr(VI) in the intestine, a 90-day drinking water study was conducted to collect histological, biochemical, toxicogenomic and pharmacokinetic data in intestinal tissues. Using MOA analyses and human relevance frameworks proposed by national and international regulatory agencies, the weight of evidence supports a cytotoxic MOA with the following key events: (a) absorption of Cr(VI) from the intestinal lumen, (b) toxicity to intestinal villi, (c) crypt regenerative hyperplasia and (d) clonal expansion of mutations within the crypt stem cells, resulting in late onset tumorigenesis. This article summarizes the data supporting each key event in the MOA, as well as data that argue against a mutagenic MOA for Cr(VI)-induced intestinal tumors.
    Full-text · Article · Mar 2013 · Critical Reviews in Toxicology
Show more