Foxl1-Expressing Mesenchymal Cells Constitute the Intestinal Stem Cell Niche

Abstract

Background & Aims Intestinal epithelial stem cells that express Lgr5 and/or Bmi1 continuously replicate and generate differentiated cells throughout life1. Previously, Paneth cells were suggested to constitute an epithelium-intrinsic niche that regulates the behavior of these stem cells2. However, ablating Paneth cells has no effect on maintenance of functional stem cells3-5. Here, we demonstrate definitively that a small subset of mesenchymal, subepithelial cells expressing the winged-helix transcription factor Foxl1 are a critical component of the intestinal stem cell niche. Methods We genetically ablated Foxl1+ mesenchymal cells in adult mice using two separate models by expressing either the human or simian diphtheria toxin receptor (DTR) under Foxl1 promoter control. Conclusions Killing Foxl1+ cells by diphtheria toxin administration led to an abrupt cessation of proliferation of both epithelial stem- and transit-amplifying progenitor-cell populations that was associated with a loss of active Wnt signaling to the intestinal epithelium. Therefore, Foxl1-expressing mesenchymal cells constitute the fundamental niche for intestinal stem cells.

Ret receptor tyrosine kinase sustains proliferation and tissue maturation in intestinal epithelia

“…These data are consistent with the previous finding that elevated Wnt signalling promotes FEnS to organoid maturation (Fordham et al , 2013) and is reminiscent of the Wnt11/Ret autoregulatory loop promoting ureteric branching during kidney development (Majumdar et al , 2003). The relevant source of Wnt driving tissue maturation is currently unknown and is most likely not epithelial (Farin et al ., 2012; Kabiri et al , 2014; San Roman et al , 2014; Aoki et al , 2016; Valenta et al , 2016). Our Drosophila finding that Wg ligand upregulation is not transcriptional underscores the importance of considering tissue crosstalk and non‐autonomous signalling in any future studies addressing Wnt contributions to epithelial maturation in mice.…”

Myofibroblasts are distinguished from activated skin fibroblasts by the expression of AOC3 and other associated markers

“…Fine definitions of fibroblasts have been described in the skin (49) and lung (50), and a similar complexity might well exist in the gut. While this paper was under review, Aoki et al (51) described a small, Foxl1-expressing subset of subepithelial fibroblasts that appear to play an important role in the maintenance of the villus structure in the mouse small intestine. Although these cells share some expression features with MFs as we have defined them, such as high levels of FGF2, WNT5a, and GREM1 expression, our MFs do not express FOXL1 and so are a different cell type.…”

Regulation and plasticity of intestinal stem cells during homeostasis and regeneration

“…Indeed, Wnt3 knockout intestinal organoids can be rescued by co-culturing them with mesenchyme (Farin et al, 2012). Removal of Foxl1-expressing peri-cryptal mesenchymal cells in vivo causes loss of Wnt activity, and of proliferation, in crypts (Aoki et al, 2016). This recent study identifies the mesenchyme as a crucial component of the CBC niche, though it remains to be determined whether Wnt itself or another signal is non-redundant with the Paneth cell niche function.…”