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

Abstract

SummaryTissue regeneration requires dynamic cellular adaptation to the wound environment. It is currently unclear how this is orchestrated at the cellular level and how cell fate is affected by severe tissue damage. Here we dissect cell fate transitions during colonic regeneration in a mouse dextran sulfate sodium (DSS) colitis model, and we demonstrate that the epithelium is transiently reprogrammed into a primitive state. This is characterized by de novo expression of fetal markers as well as suppression of markers for adult stem and differentiated cells. The fate change is orchestrated by remodeling the extracellular matrix (ECM), increased FAK/Src signaling, and ultimately YAP/TAZ activation. In a defined cell culture system recapitulating the extracellular matrix remodeling observed in vivo, we show that a collagen 3D matrix supplemented with Wnt ligands is sufficient to sustain endogenous YAP/TAZ and induce conversion of cell fate. This provides a simple model for tissue regeneration, implicating cellular reprogramming as an essential element.

Atoh1 + secretory progenitors possess renewal capacity independent of Lgr5 + cells during colonic regeneration

“…This suggests that, in the context of injury, the presence of additional cells within the crypt may also aid in colonic regeneration, as we and others have recently proposed (Yui et al, 2018). This suggests that, in the context of injury, the presence of additional cells within the crypt may also aid in colonic regeneration, as we and others have recently proposed (Yui et al, 2018).…”

Cellular mechanisms of epithelial stem cell self‐renewal and differentiation during homeostasis and repair

“…Thus, the mouse intestinal epithelium may repurpose certain aspects of fetal transcriptional programs for regeneration. A similar phenomenon is observed in the colonic epithelium, where after injury, the tissue begins expressing SCA1, a marker of fetal intestinal progenitors, and repressing genes associated with adult stem cell state (Yui et al, ). This reactivated fetal transcriptional program appears to be linked to YAP and TAZ, as double conditional knockout animals only express SCA1 in cells that retain YAP expression and overall exhibit impaired regeneration.…”

From single cells to tissue self‐organization

“…Cells can also sense and transduce extrinsic physical cues from the microenvironment such as cell‐packing effects. This mechanosensing capability relies on membrane tension sensing pathways such as Yap1 , Piezo and Misshapen‐Yorkie pathway . Understanding how single cells perceive tissue size and function is also essential for growth termination and for successful completion of developmental and regenerative processes.…”