Intestinal stem cells (ISCs) are confined to crypt bottoms and their progeny differentiate near crypt-villus junctions. Wnt and bone morphogenic protein (BMP) gradients drive this polarity, and colorectal cancer fundamentally reflects disruption of this homeostatic signaling. However, sub-epithelial sources of crucial agonists and antagonists that organize this BMP gradient remain obscure. Here, we couple whole-mount high-resolution microscopy with ensemble and single-cell RNA sequencing (RNA-seq) to identify three distinct PDGFRA+ mesenchymal cell types. PDGFRA(hi) telocytes are especially abundant at the villus base and provide a BMP reservoir, and we identified a CD81+ PDGFRA(lo) population present just below crypts that secretes the BMP antagonist Gremlin1. These cells, referred to as trophocytes, are sufficient to expand ISCs in vitro without additional trophic support and contribute to ISC maintenance in vivo. This study reveals intestinal mesenchymal structure at fine anatomic, molecular, and functional detail and the cellular basis for a signaling gradient necessary for tissue self-renewal.

中文翻译：

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不同的间充质细胞群产生必需的肠道 BMP 信号梯度。

肠干细胞 (ISC) 局限于隐窝底部，它们的后代在隐窝-绒毛连接处附近分化。Wnt 和骨形态发生蛋白 (BMP) 梯度驱动这种极性，结直肠癌从根本上反映了这种稳态信号的破坏。然而，组织这种 BMP 梯度的关键激动剂和拮抗剂的上皮下来源仍然不清楚。在这里，我们将整体高分辨率显微镜与整体和单细胞 RNA 测序 (RNA-seq) 相结合，以识别三种不同的 PDGFRA+ 间充质细胞类型。PDGFRA(hi) telocytes 在绒毛基部特别丰富，并提供 BMP 储层，我们发现了一个 CD81+ PDGFRA(lo) 群体，正好位于分泌 BMP 拮抗剂 Gremlin1 的隐窝下方。这些细胞被称为滋养细胞，足以在没有额外营养支持的情况下在体外扩展 ISC，并有助于在体内维持 ISC。这项研究揭示了肠间充质结构的精细解剖、分子和功能细节，以及组织自我更新所必需的信号梯度的细胞基础。