Recent studies on human inflammatory bowel diseases (IBD) have brought our attention to continued epithelial injury and impaired epithelial regeneration as their key pathophysiological features. In order to develop a novel approach for the treatment of IBD, it is important to understand the ordered process of epithelial repair and the pivotal roles for the epithelial stem cells in this process. Recently, specific molecular markers for the intestinal stem cells have been identified, and this has led to characterization of the unique properties of this population of cells. In addition, advancement in technologies to isolate and culture intestinal stem cells enhances the prospect for the use of these cells as a diagnostic tool or the source of regenerative medicine. Here I review such recent progress in intestinal epithelial stem cell research and its possible application to IBD.

View full abstract

The intestinal epithelium is the most rapidly self-renewing tissue in adult mammals. In the past, extensive efforts have been made to establish primary small intestinal culture systems. However, no defined, reproducible and robust culture system has been developed. We have identified essential growth factors to maintain intestinal stem cells in vitro and established a novel culture system for mouse and human small intestinal and colonic epithelial stem cells. In this culture system, isolated crypts form “organoid structures” with a histological hierarchy that recapitulates the in vivo intestinal epithelium. We further applied the organoid culture system to diseased epithelia, such as adenoma, adenocarcinoma and Barrett's epithelium. The organoid culture system provides a versatile platform to study intestinal epithelial cell biology and the mechanisms of gastrointestinal disease.

View full abstract

Adult stem cells have the capacity to self-renew and to regenerate tissues long-term, in both homeostasis and wound repair. Genetic lineage tracing studies have identified two principal stem cell populations in the intestine. One population consists of actively cycling Lgr5⁺ cells residing at the crypt base. The other population consists of quiescent Bmi1⁺ cells that largely reside at approximately the +4 cell position directly above the Paneth cells in the crypt. Recent studies demonstrate a functional relationship between these two intestinal stem cell (ISC) populations. This review provides an overview of ISCs and the ISC niche.

View full abstract

The intestinal epithelial cells are replaced in every three to four days. This system is maintained by self-reproduction, differentiation of the intestinal stem cells. The continuous monolayer of intestinal epithelial cells functions in innate immunity as the primary barrier against microbial colonization. Paneth cells secrete α-defensins, and they are actively involved in the innate immunity and maintain the intestinal homeostasis by controlling intestinal microbiota. In addition, recent analyses of epithelial renewal in the intestine illustrate that Paneth cells provide survival signals to crypt intestinal stem cells. Two types of intestinal stem cells, crypt base columnar (CBC) stem cell and +4 stem cell, have been identified. Lgr5 positive CBC stem cells, Bmi1 positive +4 stem cells and Paneth cells create the stem cell niche in the small intestine. In this review, recent advances in understanding the roles of Paneth cells and stem cells which involve stem cell niche, and their association of inflammatory bowel disease were discussed and summarized.

View full abstract

Inflammatory bowel disease (IBD) is potentially curable by “immune rest” and correction of the genetic predisposition inherent in allogeneic hematopoietic stem cell transplantation. However, balancing risks against benefits remains challenging. Recently, application of mesenchymal stem cells (MSCs) serving as a site-regulated “drugstore” is a new concept which creates the possibility of an alternative treatment for many intractable diseases, such as IBD. Depending on the required function of MSC as a cell provider, immune moderator, and/or trophic resource, MSC therapy should be optimized; surprisingly, therapeutic effects do not always require full engraftment of MSCs, but rely on the capacity of MSCs to inhibit pathogenic immune responses and release trophic factors favoring tissue repair. Therefore, optimization of pleiotropic gut trophic factors produced by MSCs must directly enhance new drug discovery for IBD.
Stem cell biology holds great promise for a new era of cell-based therapy, sparking considerable interest among scientists, clinicians, and their patients. However, the translational arm of stem cell science is in a relatively primitive state. Although several clinical studies using MSCs have been initiated, the early results suggest several inherent problems. In all of them, optimization of MSC therapy appears to be the most urgent problem, to be resolved only by scientifically unveiling the mechanisms of therapeutic action. The authors believe that such information would facilitate the critical steps in the paradigm shift from stem cell biology to regenerative medicine for conquering IBD in near future.

View full abstract

The development of colorectal cancer caused by chronic inflammatory bowel disease (IBD) is the representative example of inflammation-associated carcinogenesis. The mechanism underlying the development of colorectal cancers through chronic inflammation, however, is not known. Activation-induced cytidine deaminase (AID) was originally identified as an inducer of somatic hypermutation in the immunoglobulin gene. We recently demonstrated that the mutagenic activity of AID expression links colonic inflammation to the development of colitis associated colorectal cancers. Immunohistochemistry revealed enhanced expression of endogenous AID protein not only in the inflamed colonic mucosa of ulcerative colitis patients, but also in tumor lesions of colitis-associated colorectal cancers. Pro-inflammatory cytokine TNF-α and/or T helper cell-2-driven cytokines IL-4 and IL-13 induced strong aberrant expression of AID in human colonic epithelial cells. In vivo, aberrant AID expression in the inflamed colon is associated with the accumulation of somatic mutations in tumor suppressor Trp53 gene, and AID deficiency resulted in a reduced incidence of colitis-associated colon cancers. These findings suggested that pro-inflammatory cytokine-mediated aberrant expression of AID in colonic epithelial cells plays a role as a genotoxic factor that enhances genetic instability during chronic colonic inflammation, leading to colitis-associated colorectal cancer development.

View full abstract