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

TitleLymphatics act as a signaling hub to regulate intestinal stem cell activity.
Publication TypeJournal Article
Year of Publication2022
AuthorsNiec RE, Chu T, Schernthanner M, Gur-Cohen S, Hidalgo L, Pasolli HAmalia, Luckett KA, Wang Z, Bhalla SR, Cambuli F, Kataru RP, Ganesh K, Mehrara BJ, Pe'er D, Fuchs E
JournalCell Stem Cell
Date Published2022 Jul 07
KeywordsCell Proliferation, Intestinal Mucosa, Intestines, Organoids, Signal Transduction, Stem Cells, Wnt Proteins

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.

Alternate JournalCell Stem Cell
PubMed ID35728595
PubMed Central IDPMC9271639
Grant ListUL1 TR001866 / TR / NCATS NIH HHS / United States
P30 CA008748 / CA / NCI NIH HHS / United States
K08 CA230213 / CA / NCI NIH HHS / United States
R01 AR050452 / AR / NIAMS NIH HHS / United States
R01 HL151388 / HL / NHLBI NIH HHS / United States
R37 CA266185 / CA / NCI NIH HHS / United States
KL2 TR001865 / TR / NCATS NIH HHS / United States
T32 GM007739 / GM / NIGMS NIH HHS / United States

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