Lymphatics act as a signaling hub to regulate intestinal stem cell activity

Cell Stem Cell. 2022 Jul 7;29(7):1067-1082.e18. doi: 10.1016/j.stem.2022.05.007. Epub 2022 Jun 20.

Abstract

Barrier epithelia depend upon resident stem cells for homeostasis, defense, and repair. Epithelial stem cells of small and large intestines (ISCs) respond to their local microenvironments (niches) to fulfill a continuous demand for tissue turnover. The complexity of these niches and underlying communication pathways are not fully known. Here, we report a lymphatic network at the intestinal crypt base that intimately associates with ISCs. Employing in vivo loss of function and lymphatic:organoid cocultures, we show that crypt lymphatics maintain ISCs and inhibit their precocious differentiation. Pairing single-cell and spatial transcriptomics, we apply BayesPrism to deconvolve expression within spatial features and develop SpaceFold to robustly map the niche at high resolution, exposing lymphatics as a central signaling hub for the crypt in general and ISCs in particular. We identify WNT-signaling factors (WNT2, R-SPONDIN-3) and a hitherto unappreciated extracellular matrix protein, REELIN, as crypt lymphatic signals that directly govern the regenerative potential of ISCs.

Keywords: REELIN; RSPO3; WNTs; intestinal stem cells; lymphatic:stem cell interactome; lymphatics; organoids; spatial deconvolution; spatial transcriptomics of murine large and small intestine; stem cell niches.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Cell Proliferation
  • Intestinal Mucosa / metabolism
  • Intestines*
  • Organoids
  • Signal Transduction
  • Stem Cells*
  • Wnt Proteins / metabolism

Substances

  • Wnt Proteins