Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan, United States.
Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, United States.
Am J Physiol Gastrointest Liver Physiol. 2023 Aug 1;325(2):G158-G173. doi: 10.1152/ajpgi.00092.2023. Epub 2023 Jun 20.
Wnt signaling regulates gastric stem cell proliferation and differentiation. Although similar Wnt gradients exist within the corpus and antrum of the human stomach, there are striking differences in gland architecture and disease manifestation that suggest Wnt may differentially regulate progenitor cell function in each compartment. In this study, we tested sensitivities to Wnt activation in human gastric corpus and antral organoids to determine whether progenitor cells have region-specific differences in Wnt responsiveness. Human patient-matched corpus and antral organoids were grown in the presence of varying concentrations of the Wnt pathway activator CHIR99021 to assess regional sensitivity to Wnt signaling on growth and proliferation. Corpus organoids were further studied to understand how high Wnt affected cellular differentiation and progenitor cell function. A lower concentration of CHIR99021 stimulated peak growth in corpus organoids compared with patient-matched antral organoids. Supramaximal Wnt signaling levels in corpus organoids suppressed proliferation, altered morphology, reduced surface cell differentiation, and increased differentiation of deep glandular neck and chief cells. Surprisingly, corpus organoids grown in high CHIR99021 had enhanced organoid forming potential, indicating that progenitor cell function was maintained in these nonproliferative, deep glandular cell-enriched organoids. Passaging high-Wnt quiescent organoids into low Wnt rescued normal growth, morphology, and surface cell differentiation. Our findings suggest that human corpus progenitor cells have a lower threshold for optimal Wnt signaling than antral progenitor cells. We demonstrate that Wnt signaling in the corpus regulates a bimodal axis of differentiation, with high Wnt promoting deep glandular cell differentiation and suppressing proliferation while simultaneously promoting progenitor cell function. This study demonstrates that human gastric corpus organoids have a lower Wnt signaling threshold to drive optimal growth relative to patient-matched antral organoids. Paradoxically, supramaximal Wnt levels suppress corpus organoid proliferation, yet promote differentiation toward deep glandular cell types while simultaneously enhancing progenitor cell function. These findings provide novel insights into how Wnt signaling differentially regulates homeostasis in the human gastric corpus and antrum and contextualizes patterns of Wnt activation diseases.
Wnt 信号通路调节胃干细胞的增殖和分化。尽管人类胃的体部和胃窦中存在相似的 Wnt 梯度，但在腺体结构和疾病表现方面存在显著差异，这表明 Wnt 可能在每个部位以不同的方式调节祖细胞的功能。在这项研究中，我们测试了人胃体和胃窦类器官对 Wnt 激活的敏感性，以确定祖细胞在 Wnt 反应性方面是否存在区域特异性差异。用人源匹配的胃体和胃窦类器官在不同浓度的 Wnt 通路激活剂 CHIR99021 存在的情况下进行培养，以评估 Wnt 信号对生长和增殖的区域敏感性。进一步研究胃体类器官，以了解高 Wnt 如何影响细胞分化和祖细胞功能。与患者匹配的胃窦类器官相比，较低浓度的 CHIR99021 刺激胃体类器官的峰值生长。胃体类器官中超 Wnt 信号水平抑制增殖、改变形态、减少表面细胞分化并增加深腺颈部和主细胞的分化。令人惊讶的是，在高 CHIR99021 中生长的胃体类器官具有增强的类器官形成潜力，表明在这些非增殖、富含深腺细胞的类器官中，祖细胞功能得以维持。将高 Wnt 静止的类器官传代到低 Wnt 中可以挽救正常的生长、形态和表面细胞分化。我们的发现表明，与胃窦祖细胞相比，人胃体祖细胞对最佳 Wnt 信号的阈值更低。我们证明 Wnt 信号在胃体中调节着一种二模态分化轴，高 Wnt 促进深腺细胞分化并抑制增殖，同时促进祖细胞功能。这项研究表明，与患者匹配的胃窦类器官相比，人胃体类器官对 Wnt 信号的阈值较低，可驱动最佳生长。矛盾的是，超 Wnt 水平抑制胃体类器官的增殖，但促进向深腺细胞类型的分化，同时增强祖细胞功能。这些发现为 Wnt 信号如何以不同的方式调节人胃体和胃窦的内稳态以及对 Wnt 激活疾病的模式提供了新的见解。
