Journal
CELL STEM CELL
Volume 29, Issue 7, Pages 1067-+Publisher
CELL PRESS
DOI: 10.1016/j.stem.2022.05.007
Keywords
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Categories
Funding
- Memorial Sloan Kettering Cancer Center's Integrated Genomics Operation
- Burroughs Wellcome CAMS
- National Center for Advancing Translational Sciences, NIH, through Rockefeller University [UL1 TR001866, KL2TR001865]
- Croucher Foundation, Hong Kong
- Damon Runyon Cancer Research Foundation [DRQ: 10-21]
- Rockefeller University Women & Science and Boehringer Ingelheim Fonds
- Human Frontier Science Program [LT001519/2017]
- European Molecular Biology Organization [ALTF 1239-2016]
- SU2C Convergence Award
- AACR NextGen Grant
- NIH/NIAMS [R01-AR050452]
- STARR Foundation [2019-009]
- NIH/NCI Cancer Center Support Grant [P30 CA008748]
- Damon Runyon Clinical Investigator Award
- [T32GM007739]
- [R01HL151388]
- [R37CA266185]
- [K08CA230213]
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This study reveals a lymphatic network associated with intestinal stem cells (ISCs) in the small and large intestines. The crypt lymphatics maintain ISCs and prevent their premature differentiation. Using single-cell and spatial transcriptomics, lymphatics are identified as a central signaling hub for the crypt and ISCs.
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 lym-phatics maintain ISCs and inhibit their precocious differentiation. Pairing single-cell and spatial transcriptom-ics, 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 gen-eral and ISCs in particular. We identify WNT-signaling factors (WNT2, R-SPONDIN-3) and a hitherto unappre-ciated extracellular matrix protein, REELIN, as crypt lymphatic signals that directly govern the regenerative potential of ISCs.
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