Parietal cells (PCs) produce gastric acid to kill pathogens and aid digestion. Dysregulated PC census is common in disease, yet how PCs differentiate is unclear. Here, we identify the PC progenitors arising from isthmal stem cells, using mouse models and human gastric cells, and show that they preferentially express cell-metabolism regulator and orphan nuclear receptor Estrogen-related receptor gamma (Esrrg, encoding ERRγ). Esrrg expression facilitated the tracking of stepwise molecular, cellular, and ultrastructural stages of PC differentiation. Esrrg^P2ACreERT2 lineage tracing revealed that Esrrg expression commits progenitors to differentiate into mature PCs. scRNA-seq indicated the earliest Esrrg+ PC progenitors preferentially express SMAD4 and SP1 transcriptional targets and the GTPases regulating acid-secretion signal transduction. As progenitors matured, ERRγ-dependent metabolic transcripts predominated. Organoid and mouse studies validated the requirement of ERRγ for PC differentiation. Our work chronicles stem cell differentiation along a single lineage in vivo and suggests ERRγ as a therapeutic target for PC-related disorders.

壁细胞 (PC) 产生胃酸来杀死病原体并帮助消化。 PC 普查失调在疾病中很常见，但 PC 如何区分尚不清楚。在这里，我们使用小鼠模型和人胃细胞鉴定了源自峡部干细胞的 PC 祖细胞，并表明它们优先表达细胞代谢调节剂和孤儿核受体雌激素相关受体 γ（Esrrg，编码 ERRγ）。 Esrrg 表达有助于追踪 PC 分化的逐步分子、细胞和超微结构阶段。 Esrrg ^P2ACreERT2 谱系追踪显示，Esrrg 表达使祖细胞分化为成熟的 PC。 scRNA-seq 表明最早的 Esrrg+ PC 祖细胞优先表达 SMAD4 和 SP1 转录靶标以及调节酸分泌信号转导的 GTPase。随着祖细胞的成熟，ERRγ依赖性代谢转录本占主导地位。类器官和小鼠研究验证了 ERRγ 对 PC 分化的要求。我们的工作记录了体内干细胞沿单一谱系的分化，并建议 ERRγ 作为 PC 相关疾病的治疗靶点。