Col6a1+/CD201+ mesenchymal cells regulate intestinal morphogenesis and homeostasis.

Intestinal mesenchymal cells encompass multiple subsets, whose origins, functions, and pathophysiological importance are still not clear. Here, we used the Col6a1Cre mouse, which targets distinct fibroblast subsets and perivascular cells that can be further distinguished by the combination of the CD201, PDGFRα and αSMA markers. Developmental studies revealed that the Col6a1Cre mouse also targets mesenchymal aggregates that are crucial for intestinal morphogenesis and patterning, suggesting an ontogenic relationship between them and homeostatic PDGFRαhi telocytes. Cell depletion experiments in adulthood showed that Col6a1+/CD201+ mesenchymal cells regulate homeostatic enteroendocrine cell differentiation and epithelial proliferation. During acute colitis, they expressed an inflammatory and extracellular matrix remodelling gene signature, but they also retained their properties and topology. Notably, both in homeostasis and tissue regeneration, they were dispensable for normal organ architecture, while CD34+ mesenchymal cells expanded, localised at the top of the crypts, and showed increased expression of villous-associated morphogenetic factors, providing thus evidence for the plasticity potential of intestinal mesenchymal cells. Our results provide a comprehensive analysis of the identities, origin, and functional significance of distinct mesenchymal populations in the intestine.

Fibroblast Reprogramming in Gastrointestinal Cancer.

Gastrointestinal cancers are a significant cause of cancer mortality worldwide and have been strongly linked with chronic inflammation. Current therapies focus on epithelial/cancer cells; however, the importance of the tumor microenvironment in the development and treatment of the disease is also now well established. Cancer-associated fibroblasts (CAFs) are a major component of the tumor microenvironment, and are actively participating in tumor initiation, promotion and metastasis. They structurally and functionally affect cancer cell proliferation, tumor immunity, angiogenesis, extracellular matrix remodeling and metastasis through a variety of signaling pathways. CAFs originate predominantly from resident mesenchymal cells, which are activated and reprogrammed in response to cues from cancer cells. In recent years, chronic inflammation of the gastrointestinal tract has also proven an important driver of mesenchymal cell activation and subsequent CAF development, which in turn are capable of regulating the transition from acute to chronic inflammation and cancer. In this review, we will provide a concise overview of the mechanisms that drive fibroblast reprogramming in cancer and the recent advances on the downstream signaling pathways that regulate the functional properties of the activated mesenchyme. This new mechanistic insight could pave the way for new therapeutic strategies and better prognosis for cancer patients.

Smyd3-associated regulatory pathways in cancer.

SMYD3 is a member of the SET and MYND-domain family of methyl-transferases, the increased expression of which correlates with poor prognosis in various types of cancer. In liver and colon tumors, SMYD3 is localized in the nucleus, where it interacts with RNA Pol II and H3K4me3 and functions as a selective transcriptional amplifier of oncogenes and genes that control cell proliferation and metastatic spread. Smyd3 expression has a high discriminative power for the characterization of liver tumors and positively correlates with poor prognosis. In lung and pancreatic cancer, SMYD3 acts in the cytoplasm, potentiating oncogenic Ras/ERK signaling through the methylation of the MAP3K2 kinase and the subsequent release from its inhibitor. A clinico-pathological analysis of lung cancer patients uncovers prognostic significance of SMYD3 only for first progression survival. However, stratification of patients according to their smoking history significantly expands the prognostic value of SMYD3 to overall survival and other features, suggesting that smoking-related effects saturate the clinical analysis and mask the function of SMYD3 as an oncogenic potentiator.

R-spondin 1 and noggin facilitate expansion of resident stem cells from non-damaged gallbladders.

Pioneering studies within the last few years have allowed the in vitro expansion of tissue-specific adult stem cells from a variety of endoderm-derived organs, including the stomach, small intestine, and colon. Expansion of these cells requires activation of the receptor Lgr5 by its ligand R-spondin 1 and is likely facilitated by the fact that in healthy adults the stem cells in these organs are highly proliferative. In many other adult organs, such as the liver, proliferating cells are normally not abundant in adulthood. However, upon injury, the liver has a strong regenerative potential that is accompanied by the emergence of Lgr5-positive stem cells; these cells can be isolated and expanded in vitro as organoids. In an effort to isolate stem cells from non-regenerating mouse livers, we discovered that healthy gallbladders are a rich source of stem/progenitor cells that can be propagated in culture as organoids for more than a year. Growth of these organoids was stimulated by R-spondin 1 and noggin, whereas in the absence of these growth factors, the organoids differentiated partially toward the hepatocyte fate. When transplanted under the liver capsule, gallbladder-derived organoids maintained their architecture for 2 weeks. Furthermore, single cells prepared from dissociated organoids and injected into the mesenteric vein populated the liver parenchyma of carbon tetrachloride-treated mice. Human gallbladders were also a source of organoid-forming stem cells. Thus, under specific growth conditions, stem cells can be isolated from healthy gallbladders, expanded almost indefinitely in vitro, and induced to differentiate toward the hepatocyte lineage.

Smyd3 Is a Transcriptional Potentiator of Multiple Cancer-Promoting Genes and Required for Liver and Colon Cancer Development.

Smyd3 is a protein methyltransferase implicated in cancer development. Here we show that Smyd3 expression in mice is required for chemically induced liver and colon cancer formation. In these organs Smyd3 functions in the nucleus, stimulating the transcription of several key regulators involved in cell proliferation, epithelial-mesenchymal transition, the JAK/Stat3 oncogenic pathway, as well as the Myc and Ctnnb1 oncogenes. Smyd3 interacts with H3K4Me3-modified histone tails, which facilitates its recruitment to the core promoter regions of most active genes. Smyd3 binding density on target genes positively correlates with increased RNA polymerase-II density and transcriptional outputs. Despite its widespread distribution, the transcription-potentiating function of Smyd3 is restricted to a particular set of genes, whose expression is induced specifically during carcinogenesis.