Digestive-system stem cell research including circulating and cancer stem cells and studies on the role of microbiota in various clinical entities opens up a new area of investigation in gastroenterology.
The digestive system includes the digestive tract and digestive gland. The digestive tract is composed of the oral cavity, pharynx, esophagus, stomach, small intestine, large intestine, and anus. The digestive glands include large digestive glands and plenty of small digestive glands spread over the wall of the digestive tract. The large digestive glands, such as 3-pair salivary glands, pancreas, and liver, have a secretary portion and ducts formed by gland cells to drain the excreta into the digestive tract. During a meal, after the primary digestion of saliva, the osmolarities of the food we eat can change rapidly from zero (water) to several hundred millimoles (solid meal). In response to the rapid change of the osmolality in the gastrointestinal tract, cell junctions are tight in the stomach and colon (in order not to lose water when dehydrating feces), and gastric juice or other kinds of digestive fluids will be secreted to balance the osmolarity of gastric content. When the content comes to the small intestine, most water will be absorbed with solutes and nutrition. When it comes to the colon, the content is further dehydrated and forms feces.
The evidence is mounting that not only eukaryotic cells but also gut microbiota may release extracellular microvesicles that are absorbed from the gut into the portal and systemic circulation. Linking the fields of stem cells, innate immunity, and microbiome research opens up new avenues to develop novel diagnostic (e.g., biomarkers), therapeutic (e.g., microbiome modulation, stem cell-based medicines), and prognostic (personalized diets) tools.
In the digestive tract, stem cells occupy specific anatomic sites called niches. Within intestinal epithelium structured into crypt-villus units, epithelial tissue-committed stem cells (TCSCs) are located in the lower parts of the intestinal crypt similarly to gastric epithelial stem cells localized in the lower parts of gastric glands. TCSCs for esophageal epithelium are in turn situated in the basal layer of epithelium. Liver stem cells are located around the so-called Hering bile ducts, and they have been named oval cells. Intestinal stem cells divide continuously and give rise to robustly proliferating transit-amplifying cells maturing to epithelial cells. The fate of mature epithelial cells is their migration to the upper part of the villus, where they undergo apoptosis and intestinal excretion. The intestinal epithelium contains lgr5-positive crypt base columnar cells (CBCs), with long-term self-renewal potential and capability of producing more mature absorptive and secretory progenitors.
Fig.1 Intestinal stem cell differentiation. (Marlicz, 2019)
Crohn's disease is a complex multifactorial inflammatory bowel disease (IBD) with complex and unclear pathogenesis. The evidence indicates a pivotal involvement of innate immunity-mediated mechanisms and defects in stem cell differentiation. Various populations of intestinal progenitor cells have been implicated in IBD pathogenesis, including Paneth and Goblet cell alterations. Of relevance, the autologous hematopoietic cell transplants as well as infusions of mesenchymal stem cells (MSCs) turned out to have beneficial effects in patients suffering from refractory Crohn's disease associated with prolonged remissions. Based on our observations, various populations of stem cells may yield novel diagnostic and therapeutic options for IBD patients.
Bone marrow-derived cells attracted to gastric mucosa could be a source of gastric malignancy under inflammatory conditions. This observation paved up the foundations of a concept of migrating cancer stem cells (CSCs). Migrating CSCs contributing to gastric malignancy could express the following surface markers: CD44, CD133 (prominin-1), ABCG2, ALDH1, LGR5, EpCAM, BMI1, CD24, OCT4, SOX2, and NANOG. In general, CSCs possess special functions, and their presence facilitates metastasis and resistance to radiotherapy and chemotherapy. Currently, targeting liver CSCs is viewed as an emerging approach for the treatment of hepatocellular carcinoma (HCC). Increased trafficking of bone marrow-derived stem cells in patients with pancreatic and stomach cancer has been reported by researchers. This mobilization was associated with the activation of promobilizing complement cascade and sphingosine-1-phosphate (S1P) in peripheral blood. The biological role of activated stem cells could result from their autocrine and endocrine effects affecting tumor vascularization and stromalization. Paracrine mechanisms could be executed through the release of extracellular microvesicles (ExMVs) from circulating stem cells. Recent research also indicates the involvement of other factors, in particular, small bioactive lipids that may direct mobilization and trafficking of stem cells to injured organs.
Colorectal cancer is one of the most common cancers in western countries, with the prevalence increasing with age. Numerous intrinsic and extrinsic factors were proposed to contribute to the development of this malignancy. It is well known that rare putative CSCs may circulate in the peripheral blood in humans with colonic malignancies. Putative colon CSCs may express the following biomarkers: CD44, CD133, ABCG2, ALDH1, LGR5, EpCAM, BMI1, CD24, CD166, CD29, SOX2, SOX9, OCT4, and DCLK1. A number of circulating stem cells (e.g., VSELs, HSCs, EPCs) has already been evaluated in peripheral blood of patients with colorectal cancer. In contrast to individuals diagnosed with pancreatic and gastric cancer, neither mobilization of early stem and progenitor cells into peripheral blood nor activation of a complement cascade was enhanced in patients with colorectal cancer.
Stem cells are involved in tissue and organ damage and repair. The current focus on gut inflammation, stem cell trafficking, and cancer development will be the source of next-generation diagnostic and therapeutic tools in gastroenterology and gastrointestinal oncology.
Nowadays, research of therapeutic strategies of stem cells focus on:
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