PMID- 35728595 OWN - NLM STAT- MEDLINE VI - 29 IP - 7 TI - Lymphatics act as a signaling hub to regulate intestinal stem cell activity. PG - 1067-1082.e18 CI - Copyright © 2022 Elsevier Inc. All rights reserved. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't PT - Research Support, N.I.H., Extramural PL - United States TA - Cell Stem Cell JT - Cell stem cell JID - 101311472 IS - 1875-9777 (Electronic) LID - S1934-5909(22)00207-7 [pii] LID - 10.1016/j.stem.2022.05.007 [doi] FAU - Niec, Rachel E AU - Niec RE AD - Robin Chemers Neustein Laboratory of Mammalian Cell Biology and Development, The Rockefeller University, New York, NY 10065, USA; Jill Roberts Center for Inflammatory Bowel Disease, Department of Gastroenterology and Hepatology, Weill Cornell Medicine, Cornell University, New York, NY 10065, USA. FAU - Chu, Tinyi AU - Chu T AD - Computational and Systems Biology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. FAU - Schernthanner, Marina AU - Schernthanner M AD - Robin Chemers Neustein Laboratory of Mammalian Cell Biology and Development, The Rockefeller University, New York, NY 10065, USA. FAU - Gur-Cohen, Shiri AU - Gur-Cohen S AD - Robin Chemers Neustein Laboratory of Mammalian Cell Biology and Development, The Rockefeller University, New York, NY 10065, USA. FAU - Hidalgo, Lynette AU - Hidalgo L AD - Robin Chemers Neustein Laboratory of Mammalian Cell Biology and Development, The Rockefeller University, New York, NY 10065, USA. FAU - Pasolli, Hilda Amalia AU - Pasolli HA AD - Electron Microscopy Resource Center, The Rockefeller University, New York, NY 10065, USA. FAU - Luckett, Kathleen A AU - Luckett KA AD - Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Weill Cornell Medicine, Rockefeller University, Sloan Kettering Tri-Institutional MD-PhD Program, New York, NY 10065, USA. FAU - Wang, Zhong AU - Wang Z AD - School of Software Technology, Dalian University of Technology, Dalian 116622, China. FAU - Bhalla, Sohni R AU - Bhalla SR AD - Center for Vascular and Developmental Biology, Feinberg Cardiovascular and Renal Research Institute, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA. FAU - Cambuli, Francesco AU - Cambuli F AD - Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. FAU - Kataru, Raghu P AU - Kataru RP AD - Department of Surgery, Division of Plastic and Reconstructive Surgery, Memorial Sloan Kettering Cancer Center (MSKCC), New York, NY 10065, USA. FAU - Ganesh, Karuna AU - Ganesh K AD - Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. FAU - Mehrara, Babak J AU - Mehrara BJ AD - Department of Surgery, Division of Plastic and Reconstructive Surgery, Memorial Sloan Kettering Cancer Center (MSKCC), New York, NY 10065, USA. FAU - Pe'er, Dana AU - Pe'er D AD - Computational and Systems Biology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Howard Hughes Medical Institute, New York, NY 10065, USA. Electronic address: peerd@mskcc.org. FAU - Fuchs, Elaine AU - Fuchs E AD - Robin Chemers Neustein Laboratory of Mammalian Cell Biology and Development, The Rockefeller University, New York, NY 10065, USA; Howard Hughes Medical Institute, New York, NY 10065, USA. Electronic address: fuchslb@rockefeller.edu. IS - 1875-9777 (Linking) RN - 0 (Wnt Proteins) SB - IM MH - Cell Proliferation MH - Intestinal Mucosa/metabolism MH - *Intestines MH - Organoids MH - Signal Transduction MH - *Stem Cells MH - Wnt Proteins/metabolism OTO - NOTNLM OT - REELIN OT - RSPO3 OT - WNTs OT - intestinal stem cells OT - lymphatic:stem cell interactome OT - lymphatics OT - organoids OT - spatial deconvolution OT - spatial transcriptomics of murine large and small intestine OT - stem cell niches PMC - PMC9271639 DCOM- 20220712 LR - 20230708 DP - 20220707 DEP - 20220620 AB - 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.