Regionalized disease prevalence is a common feature of the gastrointestinal tract. Herein, we employed regionally resolved Smart-seq3 single-cell sequencing, generating a comprehensive cell atlas of the adult mouse esophagus. Characterizing the esophageal axis, we identify non-uniform distribution of epithelial basal cells, fibroblasts, and immune cells. In addition, we demonstrate a position-dependent, but cell subpopulation-independent, transcriptional signature, collectively generating a regionalized esophageal landscape. Combining in vivo models with organoid co-cultures, we demonstrate that proximal and distal basal progenitor cell states are functionally distinct. We find that proximal fibroblasts are more permissive for organoid growth compared with distal fibroblasts and that the immune cell profile is regionalized in two dimensions, where proximal-distal and epithelial-stromal gradients impact epithelial maintenance. Finally, we predict and verify how WNT, BMP, insulin growth factor (IGF), and neuregulin (NRG) signaling are differentially engaged along the esophageal axis. We establish a cellular and transcriptional framework for understanding esophageal regionalization, providing a functional basis for epithelial disease susceptibility.

中文翻译：

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区域化细胞和基因特征控制食管上皮稳态


区域化疾病患病率是胃肠道的常见特征。在此，我们采用区域分辨的 Smart-seq3 单细胞测序，生成了成年小鼠食管的综合细胞图谱。表征食管轴，我们确定了上皮基底细胞、成纤维细胞和免疫细胞的不均匀分布。此外，我们展示了一种位置依赖性但细胞亚群无关的转录特征，共同产生区域化的食管景观。将体内 模型与类器官共培养相结合，我们证明了近端和远端基底祖细胞状态在功能上是不同的。我们发现，与远端成纤维细胞相比，近端成纤维细胞更有利于类器官生长，并且免疫细胞谱在两个维度上被区域化，其中近端-远端和上皮-基质梯度影响上皮维持。最后，我们预测并验证 WNT 、 BMP 、胰岛素生长因子 （IGF） 和神经调节蛋白 （NRG） 信号如何沿食管轴差异参与。我们建立了一个细胞和转录框架来理解食管区域化，为上皮疾病易感性提供了功能基础。