Epithelial WNT Ligands Are Essential Drivers of Intestinal Stem Cell Activation

Abstract

SUMMARY Intestinal stem cells (ISCs) maintain and repair the intestinal epithelium. While regeneration after ISC-targeted damage is increasingly understood, injury-repair mechanisms that direct regeneration following injuries to differentiated cells remain uncharacterized. The enteric pathogen, rotavirus, infects and damages differentiated cells while sparing all ISC populations, thus allowing the unique examination of the response of intact ISC compartments during injury-repair. Upon rotavirus infection in mice, ISC compartments robustly expand and proliferating cells rapidly migrate. Infection results specifically in stimulation of the active crypt-based columnar ISCs, but not alternative reserve ISC populations, as is observed after ISC-targeted damage. Conditional ablation of epithelial WNT secretion diminishes crypt expansion and ISC activation, demonstrating a previously unknown function of epithelial-secreted WNT during injury-repair. These findings indicate a hierarchical preference of crypt-based columnar cells (CBCs) over other potential ISC populations during epithelial restitution and the importance of epithelial-derived signals in regulating ISC behavior.

IL-22 induced cell extrusion and IL-18-induced pyroptosis prevent and cure rotavirus infection

“…While the role of adaptive immune-independent host defense against RV is most easily appreciated in immune compromised mice wherein RV loads decline markedly from their peak levels, it may also play a role in protecting against RV even in immune competent mice. While innate host defense against RV is likely multifactorial, and may involve type III interferon [3], our observation that RV infection increases IEC extrusion, combined with previous observation that RV infection activates intestinal stem cell proliferation suggests a role for increased IEC turnover in limiting RV infection [2].…”

“…In contrast to such severe injuries, RV infection is generally characterized by a lack of overt intestinal inflammation [15,16]. Nonetheless, we envisaged that promoting IEC proliferation and/or migration, IL-22 might reduce extent of RV infection by increasing the rate of turnover of IEC, especially cells near villus tips, which is the predominant site of RV infection [2][3][4]. We further reasoned that, perhaps IL-18 might share such actions and thus would further increase IEC proliferation and turnover.…”

“…Like IL-18/22 administration, RV infection, by itself, upregulated IEC extrusion with a marked further increase in IEC extrusion being observed by administration of IL-18/22 to RV-infected mice ( Figure 5A). This suggests that increased IEC extrusion may normally contribute to innate defense against RV [2] and that exogenously administered IL-18/22 (or flagellin) enhance this protective mechanism.…”

“…Rotavirus (RV) remains a scourge to humanity, causing severe distress to many and thousands of childhood deaths annually, particularly in developing countries wherein RV vaccines have only moderate efficacy [1]. RV is a double-stranded RNA virus that primarily infects intestinal epithelial cells (IEC) that line the villus tips of the ileum, resulting in severe life-threatening diarrhea in young children and moderate gastrointestinal distress in adults [2][3][4]. Such tropism and pathogenesis is faithfully recapitulated in RV-infected mice making the mouse model of RV useful for studying basic aspects of RV immunity and disease pathophysiology.…”

Wnt/β‐catenin‐mediated heat exposure inhibits intestinal epithelial cell proliferation and stem cell expansion through endoplasmic reticulum stress

“…Our data showed that heat exposure inhibited the Wnt/β‐catenin pathway, which was characterized by decreased expression of β‐catenin, cyclin D1, and c‐Myc and increased expression of GSK3β, and Wnt/β‐catenin reactivation by Rspo1 rescued the damaged cells. The Wnt/β‐catenin signaling is necessary for intestine regeneration, and decreased Wnt/β‐catenin activity reduces the inherent regenerative capacity probably owing to Wnt/β‐catenin pathway blockade disrupting the recruitment of stem cells to the injury site (Cosínroger et al, 2016; Subhrajit et al, 2016; Zou et al, 2018). Interestingly, ERS blocks Wnt processing and secretion by dissociating GRP78/BIP and Wnt, which an interaction essential for its correct posttranslational processing (Verras et al, 2008).…”