TNFAIP8 controls murine intestinal stem cell homeostasis and regeneration by regulating microbiome-induced Akt signaling

Jason R Goldsmith,Xinyuan Li,Arshad Ayyaz,Mingyue Li,Ryan Hood,Ali Zamani,Zienab Etwebi,Nina Spitofsky,Amanda Boggs,Youhai H Chen,Hakon Hakonarson,Ling Lu,Javier Rivera Guzman,Honghong Sun,Mayassa J Bou-Dargham,Terry Cathoupolis,Michael V Gonzalez,Jeffrey L Wrana,Elizabeth Reiner

doi:10.1038/s41467-020-16379-2

Abstract

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 have not been fully defined. Here we show that TNFAIP8 (also known as TIPE0) is a regulator of intestinal homeostasis that is vital for proper regeneration. TIPE0 functions through inhibiting basal Akt activation by the commensal microbiota via modulating membrane phospholipid abundance. Loss of TIPE0 in mice results in injury-resistant enterocytes, that are hyperproliferative, yet have regenerative deficits and are shifted towards a de-differentiated state. Tipe0−/− enterocytes show basal induction of the Clu+ regenerative program and a fetal gene expression signature marked by Sca1, but upon injury are unable to generate Sca-1+/Clu+ revSCs and could not regenerate the epithelium. This work demonstrates the role of TIPE0 in regulating the dynamic signaling that determines the injury response and enables intestinal epithelial cell regenerative plasticity.

Highlights

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
Bone marrow chimera studies using wild-type donors led to the induction of comparable I/R90′ injury in both the Wild type (WT) and TIPE2 mutant recipients, while TIPE0 mutant hosts still resisted tissue damage, like with the dextran sodium sulfate (DSS) model[14,15], suggesting that effects of TIPE2 or TIPE0 deficiency to I/R90′ injury are mediated by their specific roles in the immune or non-immune cells, respectively (Fig. 2a, b)
We found that Tipe0−/−, but not Tipe2−/−, mice were protected from I60′ injury (Fig. 2c, d), supporting a non-immune-mediated role for TIPE0 during ischemic injury

Summary

Introduction

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. This work demonstrates the role of TIPE0 in regulating the dynamic signaling that determines the injury response and enables intestinal epithelial cell regenerative plasticity. A population of intestinal stem cells, known as “fetal-like” stem cells because of their similarity to fetal intestinal stem cells[8], has been identified in adult mice that are Sca-1+ and Lgr5−, and only appear in appreciable numbers after injury[3,4] This fetal-like, Sca-1+ stemcell program appears to require functional YAP/TAZ-signaling[9], which is known to be repressed by β-catenin signaling, the central pathway mediating intestinal stemness, regeneration, and differentiation[6]. We report here that TIPE0 is a regulator of the intestinal injury response and controls intestinal cell stemness and plasticity during injury, by regulating basal Akt activation induced by the microbiota

Methods

Results

Conclusion