Department of Medical Oncology and Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Departments of Medicine, Brigham & Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
Division of Digestive and Liver Diseases, Department of Medicine and Irving Cancer Research Center, Columbia University Medical Center, New York, NY 10032, USA.
Cell Stem Cell. 2023 Apr 6;30(4):433-449.e8. doi: 10.1016/j.stem.2023.03.004.
Signals from the surrounding niche drive proliferation and suppress differentiation of intestinal stem cells (ISCs) at the bottom of intestinal crypts. Among sub-epithelial support cells, deep sub-cryptal CD81 PDGFRA trophocytes capably sustain ISC functions ex vivo. Here, we show that mRNA and chromatin profiles of abundant CD81 PDGFRA mouse stromal cells resemble those of trophocytes and that both populations provide crucial canonical Wnt ligands. Mesenchymal expression of key ISC-supportive factors extends along a spatial and molecular continuum from trophocytes into peri-cryptal CD81 CD55 cells, which mimic trophocyte activity in organoid co-cultures. Graded expression of essential niche factors is not cell-autonomous but dictated by the distance from bone morphogenetic protein (BMP)-secreting PDGFRA myofibroblast aggregates. BMP signaling inhibits ISC-trophic genes in PDGFRA cells near high crypt tiers; that suppression is relieved in stromal cells near and below the crypt base, including trophocytes. Cell distances thus underlie a self-organized and polar ISC niche.
周围龛位的信号驱动肠干细胞（ISCs）在肠隐窝底部的增殖并抑制其分化。在黏膜下支持细胞中，深隐窝 CD81 PDGFRA 滋养细胞能够在体外维持 ISC 的功能。在这里，我们表明丰富的 CD81 PDGFRA 小鼠基质细胞的 mRNA 和染色质图谱与滋养细胞相似，并且这两种群体都提供关键的经典 Wnt 配体。间充质表达的关键 ISC 支持因子沿着空间和分子连续体从滋养细胞延伸到隐窝周围的 CD81 CD55 细胞，这些细胞在类器官共培养物中模拟滋养细胞的活性。必需龛位因子的分级表达不是细胞自主的，而是由骨形态发生蛋白（BMP）分泌的 PDGFRA 肌成纤维细胞聚集体的距离决定的。BMP 信号在靠近高隐窝层的 PDGFRA 细胞中抑制 ISC-滋养基因；这种抑制在靠近和低于隐窝基底的基质细胞中得到缓解，包括滋养细胞。因此，细胞距离是自我组织和极化的 ISC 龛位的基础。
