Intestinal myofibroblasts regulate intestinal epithelial cell plasticity via YAP/TAZ

Abstract

Intestinal stromal cells play a key role as the crypt niche cells during epithelial homeostasis and tumor initiation. However, the underlying cellular and molecular mechanisms remain unclear. We developed various types of three-dimensional (3D) tissue culture models to culture small intestinal myofibroblasts (SI MFs) together with enteroids. SI MFs significantly enhanced self-renewal, lumen formation and survival of enteroids, that was mediated via a paracrine mechanism in a Wnt-independent manner. Such co-cultured enteroids resembled SI organoids derived from Apc+/1638N tumors. Microarray analysis showed upregulation of genes associated with YAP signaling in enteroids co-cultured with SI MFs, which was confirmed by protein quantification by mass spectrometry and could be correlated with findings from human colorectal tumor specimens. Mass spectrometric analysis of conditioned media and inhibitor studies pointed to a role for TGF-{beta} in the SI MF-SI epithelium cross-talk. Altogether, utilizing different 3D stroma-epithelium co-culture models, we demonstrate here that SI MFs have the potential to induce a tumor-like phenotype in the intestinal crypts via a paracrine mechanism, that involves YAP and TGF-{beta}, but not canonical Wnt signaling.