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.
Computational and Systems Biology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Cell Stem Cell. 2022 Jul 7;29(7):1067-1082.e18. doi: 10.1016/j.stem.2022.05.007. Epub 2022 Jun 20.
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.
屏障上皮依赖于常驻干细胞来维持其体内平衡、防御和修复。小肠和大肠的上皮干细胞（ISCs）响应其局部微环境（龛），以满足组织更新的持续需求。这些龛的复杂性和潜在的通讯途径尚未完全了解。在这里，我们报告了在肠隐窝基底处存在一个与 ISCs 密切相关的淋巴网络。通过体内功能丧失和淋巴：类器官共培养实验，我们表明隐窝中的淋巴管维持 ISCs 并抑制其过早分化。通过单细胞和空间转录组学，我们应用贝叶斯分析来解卷积空间特征内的表达，并开发 SpaceFold 来以高分辨率稳健地绘制龛位，揭示淋巴管是隐窝的核心信号枢纽，特别是对 ISCs 而言。我们发现 WNT 信号因子（WNT2、R-SPONDIN-3）和一个以前未被重视的细胞外基质蛋白 REELIN，作为直接控制 ISCs 再生潜力的隐窝淋巴管信号。
