T Helper Cell Cytokines Modulate Intestinal Stem Cell Renewal and Differentiation

Abstract

Summary In the small intestine, a niche of accessory cell types supports the generation of mature epithelial cell types from intestinal stem cells (ISCs). It is unclear however if and how immune cells in the niche affect ISC fate or the balance between self-renewal and differentiation. Here, we use single-cell RNA-seq to identify MHC class II (MHCII) machinery enrichment in two subsets of Lgr5+ ISCs. We show that MHCII+ Lgr5+ ISCs are non-conventional antigen presenting cells in co-cultures with CD4+ T helper (Th) cells. Stimulation of intestinal organoids with key Th cytokines affects Lgr5+ ISC renewal and differentiation in opposing ways: pro-inflammatory signals promote differentiation, while regulatory cells and cytokines reduce it. In vivo genetic perturbation of Th cells or MHCII expression on Lgr5+ ISCs impacts epithelial cell differentiation and IEC fate during infection. These interactions between Th cells and Lgr5+ ISCs thus orchestrate tissue-wide responses to external signals.

Lgr5+ telocytes are a signaling hub at the intestinal villus tip

“…Lgr5+ fibroblasts have previously been identified in the lung 37 , suggesting that Lgr5+ stromal cells may constitute a localized mesenchymal niche component in other tissues. It will be important to use similar spatial transcriptomics approaches to explore the cross-talk between the mesenchymal cell populations and zonated immune cell populations 25 as well as other stromal components such as enteric neurons 26 Figure S1 -Zonated expression of stromal ligands (a) and receptors (b). Il18r1 marked in red.…”

“…We next sought to obtain the global gene expression signatures of Lgr5+ VTTs and of other intestinal mesenchymal cell populations. LCMseq provides a spatial map of gene expression along the crypt villus axis, however each zone represents a mixture of diverse cell types, including mesenchymal cells, endothelial cells, immune cells 25 and enteric neurons 26 .…”

“…We used the single cell RNAseq data of Biton et al 25 (6558 cells annotated as WT control, Fig. S1c).…”

Reactions Coupled Self‐ and Co‐Assembly: A Highly Dynamic Process and the Resultant Spatially Inhomogeneous Structure

“…[5][6][7][8] The complexity includes not only the hierarchical structures throughout all length scales, but also their highly dynamic adaptiont ot he environments.T he representative example is the stem cells, which can develop into differentt issues or organs depending on the environments. [9][10][11][12] It is highly important to develop artificial systems that can develop into different structures from the same startingm aterials upon the change of environments to help to understand such mystery phenomenona nd construct artificial intelligent systems. It has to be mentioned that the highly adaptive systemsh ere have inherentd ifferences from the ubiquitous systems in which different conditions lead to different products.…”

Evolution of gastrointestinal tract morphology and plasticity in cave-adapted Mexican tetra, Astyanax mexicanus

“…High-fat diet alters these pathways to favor self-renewal and secretory cell formation (2,3). Cytokine signals from tissue-resident immune cells can also promote stem cell renewal in response to infection (4,5). While studies utilizing model organisms and organoid culture have begun to reveal how homeostasis of the epithelium is maintained, there is a limited understanding of how these pathways have evolved in response to different diets.…”