YAP/TAZ-Dependent Reprogramming of Colonic Epithelium Links ECM Remodeling to Tissue Regeneration

摘要

class="head no_bottom_margin" id="sec1title">IntroductionIntestinal epithelial stem cells ensure fast tissue replenishment. These adult stem cells reside at the bottom of crypts and express markers such as Lgr5, Olfm4, and Lrig1 (). Upon tissue damage, cells that are distinct from adult intestinal stem cells contribute to wound repair, replenishment of lost stem cells, and restoration of tissue architecture (). Yet, the cellular responses underlying this remarkable plasticity remain unclear.Patients with inflammatory bowel disease, such as ulcerative colitis (UC) and Crohn’s disease, have impaired intestinal barrier function, and they experience recurrent severe inflammation. Current treatment strategies aim to reduce the intestinal inflammation burden in general, with only a limited focus on targeting the epithelium to promote tissue regeneration. Tissue regeneration is a complex process associated with pronounced changes to the environment at both the cellular and biophysical levels (). Sensing these environmental changes and spatial information is, however, essential during tissue regeneration. Two highly related transcriptional activators, YAP and TAZ, have recently emerged as primary sensors of the cellular microenvironment, integrating cell polarity and mechanical cues with growth factor signaling and inflammation (). In vitro, activation of YAP/TAZ has recently been shown to dedifferentiate committed cells back to a progenitor and stem cell state (). YAP/TAZ-mediated signaling appears dispensable during steady-state homeostasis in the intestinal epithelium (, , ). Evidence does, however, suggest an important role of YAP during intestinal regeneration (). Yet, it remains largely unknown how YAP/TAZ signaling is controlled during repair and which cellular processes are regulated by YAP/TAZ during tissue remodeling.Here we examine wound repair in the colonic epithelium and identify markers for the repairing epithelium (RE). Characterization of the repairing epithelium demonstrates a strong and necessary response by the transcriptional regulators YAP/TAZ driven by environmental changes. We provide evidence that this can be recapitulated in vitro using defined cell culture conditions in a YAP/TAZ-dependent manner. Moreover, the changes associated with the repairing epithelium strongly suggest that the tissue undergoes injury-assisted transition into a primitive state with fetal-like properties. Importantly, the changes associated with the wound-induced reprogramming are reversible both in vivo and in vitro, allowing the tissue to regain its normal cellular architecture and adult-specific gene expression, when regeneration is complete. We believe that understanding the process of tissue repair and how this is orchestrated at the cellular and molecular levels will provide better solutions for enhancing regeneration.