Intestinal Stem Cell Heterogeneity
Gastrointestinal Tract
The small and large intestines are part of the lower gastrointestinal tract. They are mostly known to be responsible for the digestion of food and absorption of nutrients (small intestine), and re-sorption of water (large intestine). Moreover, the intestinal epithelium has additional functions: specialized cells secrete metabolism-regulating hormones, while interacting with the natural microflora to modulate the immune system. Therefore, it is imperative to the well-being of the whole organism to keep the intestinal tract healthy.
The intestine is a long tube made up of a layer of smooth muscle, a connective tissue called the lamina propria, and a one-cell-thick layer of specialized epithelial cells responsible for most of the gut's functions. This epithelial cell layer is organized into villi (in the small intestine only) and crypts. Villi increase the absorptive surface of the gut, while crypts provide an appropriate niche for proliferating cells. These cells were identified as intestinal stem cells (ISCs).
Fig.1 Overview of the intestinal stem cell system. (Goodell, 2015)
ISCs Heterogeneity
Intestinal crypts are clonal units that are maintained by the division of crypt stem cells. Prior to the availability of genetic modification and transgenic mice, ISCs were examined via somatic mutational analyses. If the mutation occurs in a stem cell, the mutation will be fixed and the entire crypt will consist of mutant epithelium, according to this theory. Clonal stabilization time, often known as the time required for a complete mutant crypt to form, has been the topic of research in the mouse and human gut. Intriguingly, cell kinetics in the small and large intestines of mice have been observed. Crypts with partial mutations are not permanent. If the mutation occurs in stem cells, they either transform into fully mutant crypts or, if it occurs in TACs (Transiently Amplified Cells), they revert to their original state.
Fig.2 The ISCs compartment and mesenchymal niche cells. (Zhu, 2021)
Using Lineage-tracing experiment to Investigate ISCs Heterogeneity
The availability of transgenic mice made the direct investigation of ISC behavior feasible. Experiments on mice have demonstrated that a subpopulation of cells expressing high levels of leucine-rich repeat-containing G-protein coupled receptor 5 (Lgr5), CD133, Bmi1, or mTert (telomerase reverse transcriptase) can repopulate the entire intestinal crypts, as indicated by the specific stem cell marker. In addition, unique marking patterns have been discovered in a lineage-tracing experiment including constantly marked crypts. In contrast, others inside a crypt are either discontinuously marked or have a small number of marked cells from short V-shaped formations. This is suggestive of varied stem cell activity levels in various crypts.
Fig.3 Refined models of the intestinal epithelial linage hierarchy. (Capdevila, 2021)
Niche Succession and ISCs Heterogeneity
Niche succession, i.e., the progeny of a single stem cell dominating the whole crypt, is also suggestive of intercryptal stem cell heterogeneity. Single-cell imaging revealed that the stemness of ISCs is determined by their proximity to Paneth cells. Using multiphoton intravital microscopy through an abdominal imaging window, scientists have examined the spatial heterogeneity of Lgr5+ ISCs at the single-cell level. It has been discovered that stem cells rearrange themselves after a division, eliminating the border ISCs from the 'niche'. Additionally, it was noted that the position of the ISC within the crypt was a determinant of its potential for self-renewal.
Fig.4 A niche succession sequence. (Leedham, 2005)
Heterogeneity of ISCs Along the Intestinal Tract
Regional variations in crypt size, proliferative index, and the placement of proliferative cells along the crypt axis have been reported. For example, the ascending colon's crypt length is considerably less than that of the transverse and descending colons. In addition, the ascending colon has a significantly smaller total number of proliferative cells than other colon segments. In addition to the duration of mitosis and the apoptotic index following irradiation, additional alterations are proposed. There are also regional changes in the gene expression levels of stem cell-related genes and Wnt pathway modulators along the digestive tract. In addition, only 10% of the crypts in the small intestine have a non-Paneth label-retaining cell, and 0.1% contain two. Stem cells appear to vary along the digestive tract in general.
Fig.5 The structure and homeostatic maintenance of the intestinal epithelium, including small and large intestines. (Wang, 2022)
References
- Goodell, M.A.; et al. Somatic stem cell heterogeneity: diversity in the blood, skin and intestinal stem cell compartments. Nature Reviews Molecular Cell Biology. 2015, 16: 299-309.
- Zhu, G.L.; Xi, R.W. The cellular niche for intestinal stem cells: a team effort. Cell Regeneration. 2021, 10: 1.
- Capdevila, C.; et al. Cellular origins and lineage relationships of the intestinal epithelium. American Journal of Physiology – Gastrointestinal and Liver Physiology. 2021, 321(4): G413-G425.
- Leedham, S.J.; et al. Gastrointestinal stem cells and cancer: bridging the molecular gap. Stem Cell Reviews and Reports. 2005, 1(3): 233-41.
- Wang, Y.L.; et al. Intestinal cellular heterogeneity and disease development revealed by single-cell technology. Cell Regeneration. 2022, 11: 26.
