Dr. Jason Goldsmith, University of Pennsylvania, presents this seminar presented by the department of biology.

About the Seminar

The intestine is a highly dynamic environment that requires tight control of the various inputs to maintain homeostasis and allow for proper responses to injury. It was recently found that the stem cell niche and epithelium is regenerated after injury by de-differentiated adult cells, through a process that gives rise to Sca1+ fetal-like cells and is driven by a transient population of Clu+ revival stem cells (revSCs). However, the molecular mechanisms that regulate this dynamic process are largely unexplored. Here we show that TNFAIP8 is a crucial regulator of homeostasis that is vital for proper regeneration after inflammatory injury.  TNFAIP8 functions through inhibiting basal Akt activation by the commensal microbiota via modulating membrane phospholipid levels. Loss of TNFAIP8 in mice resulted in injury-resistant enterocytes, that are hyperproliferative, yet have regenerative deficits and are shifted towards a de-differentiated state. Tnfaip8-/- enterocytes showed basal induction of the Clu+ regenerative program and a fetal gene expression signature marked by Sca1, but upon injury were unable to generate bona fide Sca-1+/Clu+ revSCs and could not regenerate the epithelium. This work demonstrates the critical role of TNFAIP8 in regulating the dynamic signaling that determines the inflammatory injury response and enables intestinal epithelial cell regenerative plasticity.