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

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.

TNFAIP8 Regulates Intestinal Epithelial Cell Differentiation and May Alter Terminal Differentiation of Secretory Progenitors

“…Clusters representing each of the cell types found in the ileal epithelium were identified as well as a cluster in each sample representing intraepithelial lymphocytes (Figure 1a). TIPE0 −/− mice had similar or decreased levels of terminally differentiated enterocytes and increased levels of transitional/partially differentiated and Lgr5+ stem cells, consistent with previous studies (Figure 1b) [22]. Goblet cells were significantly enriched in the TIPE0 −/− intestine, which is also consistent with previous findings by Goldsmith et al These data further suggest that differentiation in the TIPE0 −/− intestine is dysregulated, with a shift from terminally differentiated enterocytes towards Lgr5+ stem cells and transitional enterocytes with the notable exception of goblet cells.…”

“…TIPE0, as well as other members of the TIPE family, has been found to interact with a variety of phospholipids, including phosphatidylinositol-4-phosphate (PI4P), PI (4,5) P2, PI (3,5) P2, PI (3,4) P2, and PI (3,4,5) P3 through a large hydrophobic TIPE homology (TH) domain [18][19][20]. Through binding to PIPs, TIPE0 plays an important role in modulating Pre-processing of droplet (10X) scRNA-seq data including demultiplexing, alignment to the mm10 transcriptome, and UMI-collapsing was performed by Goldsmith et al [22]. 10X genomics output was loaded into R as a cell data set (CDS) object using the "load_mm_data" function from the Monocle3 package.…”

“…The processed data was normalized by logarithmic and size factors to address differences in sequencing depth followed by dimensionality reduction by Principal Component Analysis (PCA) using the Monocle3 function "preprocess_cds". Fourteen principal components were used as described in Goldsmith et al [22]. The dimensionality of the data was further reduced for visualization by using Uniform Manifold Approximation and Projection (UMAP).…”

Subversion of Niche-Signalling Pathways in Colorectal Cancer: What Makes and Breaks the Intestinal Stem Cell

“…The lipid transporter TIPE0 (also known as TNFAIP8) has recently been recognized as an important regulator of the Clu + regenerative program, with Tipe0 −/− mice exhibiting poor recovery from DSS-induced injury and reduced subsequent survival [ 157 ]. Underlying this phenotype is a broad dysfunction of plasticity programs, characterized by an overabundance of Lgr5 + ISCs and partially differentiated cells in homeostasis, and an impaired capacity to dedifferentiate post injury.…”

“…Underlying this phenotype is a broad dysfunction of plasticity programs, characterized by an overabundance of Lgr5 + ISCs and partially differentiated cells in homeostasis, and an impaired capacity to dedifferentiate post injury. Indeed, although Tipe0 −/− enterocytes are induced to proliferate post injury, they fail to recruit YAP to the nucleus and are hence impeded from mounting a Sca1 + Clu + regenerative response, leading to intestinal demise [ 157 ].…”