Secreted stromal protein ISLR promotes intestinal regeneration by suppressing epithelial Hippo signaling

Abstract

The Hippo–YAP signaling pathway plays an essential role in epithelial cells during intestinal regeneration and tumorigenesis. However, the molecular mechanism linking stromal signals to YAP‐mediated intestinal regeneration and tumorigenesis is poorly defined. Here, we report a stroma–epithelium ISLR–YAP signaling axis essential for stromal cells to modulate epithelial cell growth during intestinal regeneration and tumorigenesis. Specifically, upon inflammation and in cancer, an oncogenic transcription factor ETS1 in stromal cells induces expression of a secreted protein ISLR that can inhibit Hippo signaling and activate YAP in epithelial cells. Deletion of Islr in stromal cells in mice markedly impaired intestinal regeneration and suppressed tumorigenesis in the colon. Moreover, the expression of stromal cell‐specific ISLR and ETS1 significantly increased in inflamed mucosa of human IBD patients and in human colorectal adenocarcinoma, accounting for the epithelial YAP hyperactivation. Collectively, our findings provide new insights into the signaling crosstalk between stroma and epithelium during tissue regeneration and tumorigenesis.

Plasticity of Paneth cells and their ability to regulate intestinal stem cells

“…The matrix-mediated integrin signalling via YAP/TAZ mechano-transduction promotes intestine regeneration in collagen type I; this process is accompanied by Wnt activation, and the same phenomenon was observed in human ulcerative colitis [44]. ISLR has been identified as a marker of mesenchymal stromal cells [45] because it can downregulate Hippo signals for YAP activation to promote intestine regeneration [46]. Mesenchymal stem cells (MSCs) have a significant therapeutic potential for tissue damage by improving the growth of intestinal crypts in vitro by activating the Wnt/β-catenin signalling pathway [47].…”

Regenerative Intestinal Stem Cells Induced by Acute and Chronic Injury: The Saving Grace of the Epithelium?

“…Islr was previously shown to maintain an undifferentiated state of stromal cells ( Maeda et al, 2016 ). In this study, Xu et al (2020) found that Islr inhibits Lats, leading to increased Yap activity. They then used a stromal cell conditional KO mouse model targeting Islr, in order to understand its role in modulating the Hippo signaling pathway during homeostasis and damage.…”

“… Romera-Hernández et al (2020) induced intestinal injury using methotrexate, and found that group 3 innate lymphoid cells (ILC3s) drive intestinal epithelial repair in a Yap1 dependent manner, but independent of intestinal regenerative IL-22. Xu et al (2020) examined the role of the stromal cell protein ISLR [immunoglobulin (Ig)-like domain and five leucine-rich repeat (LRR) domains], in recovery from DSS and TNBS injury in mice. Islr was previously shown to maintain an undifferentiated state of stromal cells ( Maeda et al, 2016 ).…”

MiR-22 modulates brown adipocyte thermogenesis by synergistically activating the glycolytic and mTORC1 signaling pathways

“…H&E staining, immunofluorescence, IHC and western blotting were performed as we previously described 31 . The BAT was rinsed with PBS, fixed in 4% PFA, paraffin-embedded, sectioned at 5 μm and stained with H&E. For immunohistochemical staining, antigen retrieval was performed by heating the slides to 95 °C for 20 min in 0.01 M citrate buffer (pH 6.0) in a microwave.…”