Wnt Ligands as a Part of the Stem Cell Niche in the Intestine and the Liver

The term "Wnt signaling" does not refer to one uniform signal transduction cascade. Instead, it describes the multiple discrete signals elicited by Wnt ligands following their interaction with distinct receptor complexes. The interaction of stem cells with niche cells is coordinated by the involvement of different signaling pathways, including Wnt signaling. The stem cell populations are highly sensitive to modulation of Wnt pathway activity. Wnt signaling is of paramount importance for stem cell self-renewal, survival, proliferation, differentiation, movement, and cell polarity. Aberrant activation of Wnt/β-catenin signaling is associated with the pathology of many types of cancer, such as colorectal cancer and hepatocellular carcinoma. Importantly, although often initiated by mutation(s) downstream of the Wnt-receptor complex, the progression of colorectal cancer still seems to be augmented by Wnt ligand-mediated signaling. This chapter focuses on the role of Wnt ligands in the intestine and the liver during homeostasis and cancer

GLI1-expressing mesenchymal cells form the essential Wnt-secreting niche for colon stem cells

Wnt-β-catenin signalling plays a pivotal role in the homeostasis of the intestinal epithelium by promoting stem cell renewal. In the small intestine, epithelial Paneth cells secrete Wnt ligands and thus adopt the function of the stem cell niche to maintain epithelial homeostasis. It is unclear which cells comprise the stem cell niche in the colon. Here we show that subepithelial mesenchymal GLI1-expressing cells form this essential niche. Blocking Wnt secretion from GLI1-expressing cells prevents colonic stem cell renewal in mice: the stem cells are lost and, as a consequence, the integrity of the colonic epithelium is corrupted, leading to death. GLI1-expressing cells also play an important role in the maintenance of the small intestine, where they serve as a reserve Wnt source that becomes critical when Wnt secretion from epithelial cells is prevented. Our data suggest a mechanism by which the stem cell niche is adjusted to meet the needs of the intestine via adaptive changes in the number of mesenchymal GLI1-expressing cells

Wnt ligands secreted by subepithelial mesenchymal cells are essential for the survival of intestinal stem cells and gut homeostasis

Targeting of Wnt signaling represents a promising anti-cancer therapy. However, the consequences of systemically attenuating the Wnt pathway in an adult organism are unknown. Here, we globally prevent Wnt secretion by genetically ablating Wntless. We find that preventing Wnt signaling in the entire body causes mortality due to impaired intestinal homeostasis. This is caused by the loss of intestinal stem cells. Reconstitution of Wnt/β-catenin signaling via delivery of external Wnt ligands prolongs the survival of intestinal stem cells and reveals the essential role of extra-epithelial Wnt ligands for the renewal of the intestinal epithelium. Wnt2b is a key extra-epithelial Wnt ligand capable of promoting Wnt/β-catenin signaling and intestinal homeostasis. Wnt2b is secreted by subepithelial mesenchymal cells that co-express either Gli1 or Acta2. Subepithelial mesenchymal cells expressing high levels of Wnt2b are predominantly Gli1 positive

Epithelial Wnt secretion drives the progression of inflammation-induced colon carcinoma in murine model

Colon cancer is initiated by stem cells that escape the strict control. This process is often driven through aberrant activation of Wnt signaling by mutations in components acting downstream of the receptor complex that unfetter tumor cells from the need for Wnts. Here we describe a class of colon cancer that does not depend on mutated core components of the Wnt pathway. Genetically blocking Wnt secretion from epithelial cells of such tumors results in apoptosis, reduced expression of colon cancer markers, followed by enhanced tumor differentiation. In contrast to the normal colonic epithelium, such tumor cells autosecrete Wnts to maintain their uncontrolled proliferative behavior. In humans, we determined certain cases of colon cancers in which the Wnt pathway is hyperactive, but not through mutations in its core components. Our findings illuminate the path in therapy to find further subtypes of Wnt-dependent colon cancer that might be responsive to Wnt secretion inhibitors

Atrial Fibrillation Management in Acute Stroke Patients in Türkiye: Real-life Data from the NöroTek Study

Objective: Atrial fibrillation (AF) is the most common directly preventable cause of ischemic stroke. There is no dependable neurology-based data on the spectrum of stroke caused by AF in Turkiye. Within the scope of NoroTek-Turkiye (TR), hospital-based data on acute stroke patients with AF were collected to contribute to the creation of acute-stroke algorithms.Materials and Methods: On May 10, 2018 (World Stroke Awareness Day), 1,790 patients hospitalized at 87 neurology units in 30 health regions were prospectively evaluated. A total of 929 patients [859 acute ischemic stroke, 70 transient ischemic attack (TIA)] from this study were included in this analysis.Results: The rate of AF in patients hospitalized for ischemic stroke/TIA was 29.8%, of which 65% were known before stroke, 5% were paroxysmal, and 30% were diagnosed after hospital admission. The proportion of patients with AF who received "effective" treatment [international normalization ratio >= 2.0 warfarin or non-vitamin K antagonist oral anticoagulants (NOACs) at a guideline dose] was 25.3%, and, either no medication or only antiplatelet was used in 42.5% of the cases. The low dose rate was 50% in 42 patients who had a stroke while taking NOACs. Anticoagulant was prescribed to the patient at discharge at a rate of 94.6%; low molecular weight or unfractionated heparin was prescribed in 28.1%, warfarin in 32.5%, and NOACs in 31%. The dose was in the low category in 22% of the cases discharged with NOACs, and half of the cases, who received NOACs at admission, were discharged with the same drug.Conclusion: NoroTekTR revealed the high but expected frequency of AF in acute stroke in Turkiye, as well as the aspects that could be improved in the management of secondary prophylaxis. AF is found in approximately one-third of hospitalized acute stroke cases in Turkiye. Effective anticoagulant therapy was not used in three-quarters of acute stroke cases with known AF. In AF, heparin, warfarin, and NOACs are planned at a similar frequency (one-third) within the scope of stroke secondary prophylaxis, and the prescribed NOAC dose is subtherapeutic in a quarter of the cases. Non-medical and medical education appears necessary to prevent stroke caused by AF