Telocytes: Active Players in the Rainbow Trout (Oncorhynchus mykiss) Intestinal Stem-Cell Niche

In order to improve the sustainability of trout farming, it is essential to develop alternatives to fish-based meals that prevent intestinal disorders and support growth performances. Therefore, an accurate knowledge of intestinal morphology and physiology is desirable. We previously described the epithelial component of the intestinal stem-cell (ISC) niche in rainbow trout (Oncorhynchus mykiss), which is one of the most successfully farmed species and a representative model of the salmonids family. This work aims to expand that knowledge by investigating the niche stromal components that contribute to intestinal homeostasis. We analyzed samples belonging to five individuals collected from a local commercial farm. Histological and ultrastructural studies revealed peculiar mesenchymal cells adjacent to the epithelium that generated an intricate mesh spanning from the folds’ base to their apex. Their voluminous nuclei, limited cytoplasm and long cytoplasmic projections characterized them as telocytes (TCs). TEM analysis showed the secretion of extracellular vesicles, suggesting their functional implication in cell-to-cell communication. Furthermore, we evaluated the localization of well-defined mouse TC markers (pdgfrα and foxl1) and their relationship with the epithelial component of the niche. TCs establish a direct connection with ISCs and provide short-range signaling, which also indicates their key role as the mesenchymal component of the stem-cell niche in this species. Interestingly, the TC distribution and gene-expression pattern in rainbow trout closely overlapped with those observed in mice, indicating that they have the same functions in both species. These results substantially improve our understanding of the mechanisms regulating intestinal homeostasis and will enable a more detailed evaluation of innovative feed effects.

INDY—From Flies to Worms, Mice, Rats, Non-Human Primates, and Humans

I’m Not Dead Yet (Indy) is a fly homologue of the mammalian SLC13A5 (mSLC13A5) plasma membrane citrate transporter, a key metabolic regulator and energy sensor involved in health, longevity, and disease. Reduction of Indy gene activity in flies, and its homologs in worms, modulates metabolism and extends longevity. The metabolic changes are similar to what is obtained with caloric restriction (dietary restriction). Similar effects on metabolism have been observed in mice and rats. As a citrate transporter, INDY regulates cytoplasmic citrate levels. Indy flies heterozygous for a P-element insertion have increased spontaneous physical activity, increased fecundity, reduced insulin signaling, increased mitochondrial biogenesis, preserved intestinal stem cell homeostasis, lower lipid levels, and increased stress resistance. Mammalian Indy knockout (mIndy-KO) mice have higher sensitivity to insulin signaling, lower blood pressure and heart rate, preserved memory and are protected from the negative effects of a high-fat diet and some of the negative effects of aging. Reducing mIndy expression in human hepatocarcinoma cells has recently been shown to inhibit cell proliferation. Reduced Indy expression in the fly intestine affects intestinal stem cell proliferation, and has recently been shown to also inhibit germ cell proliferation in males with delayed sperm maturation and decreased spermatocyte numbers. These results highlight a new connection between energy metabolism and cell proliferation. The overrall picture in a variety of species points to a conserved role of INDY for metabolism and health. This is illustrated by an association of high mIndy gene expression with non-alcoholic fatty liver disease in obese humans. mIndy (mSLC13A5) coding region mutations (e.g., loss-of-function) are also associated with adverse effects in humans, such as autosomal recessive early infantile epileptic encephalopathy and Kohlschütter−Tönz syndrome. The recent findings illustrate the importance of mIndy gene for human health and disease. Furthermore, recent work on small-molecule regulators of INDY highlights the promise of INDY-based treatments for ameliorating disease and promoting healthy aging.

Intestinal Stem Cell-on-Chip to Study Human Host-Microbiota Interaction

The gut is a tubular organ responsible for nutrient absorption and harbors our intestinal microbiome. This organ is composed of a multitude of specialized cell types arranged in complex barrier-forming crypts and villi covered by a mucosal layer controlling nutrient passage and protecting from invading pathogens. The development and self-renewal of the intestinal epithelium are guided by niche signals controlling the differentiation of specific cell types along the crypt-villus axis in the epithelium. The emergence of microphysiological systems, or organ-on-chips, has paved the way to study the intestinal epithelium within a dynamic and controlled environment. In this review, we describe the use of organ-on-chip technology to control and guide these differentiation processes in vitro. We further discuss current applications and forthcoming strategies to investigate the mechanical processes of intestinal stem cell differentiation, tissue formation, and the interaction of the intestine with the microbiota in the context of gastrointestinal diseases.

Smooth muscle-specific MMP17 (MT4-MMP) regulates the intestinal stem cell niche and regeneration after damage

Smooth muscle is an essential component of the intestine, both to maintain its structure and produce peristaltic and segmentation movements. However, very little is known about other putative roles that smooth muscle cells may have. Here, we show that smooth muscle cells may be the dominant suppliers of BMP antagonists, which are niche factors essential for intestinal stem cell maintenance. Furthermore, muscle-derived factors render epithelium reparative and fetal-like, which includes heightened YAP activity. Mechanistically, we find that the membrane-bound matrix metalloproteinase MMP17, which is exclusively expressed by smooth muscle cells, is required for intestinal epithelial repair after inflammation- or irradiation-induced injury. Furthermore, we propose that MMP17 affects intestinal epithelial reprogramming after damage indirectly by cleaving diffusible factor(s) such as the matricellular protein PERIOSTIN. Together, we identify an important signaling axis that establishes a role for smooth muscle cells as modulators of intestinal epithelial regeneration and the intestinal stem cell niche.