Metabolic regulator ERRγ governs gastric stem cell differentiation into acid-secreting parietal cells

IF 19.8 1区医学 Q1 CELL & TISSUE ENGINEERING

Cell stem cell Pub Date : 2024-05-10 DOI:10.1016/j.stem.2024.04.016

Mahliyah Adkins-Threats, Sumimasa Arimura, Yang-Zhe Huang, Margarita Divenko, Sarah To, Heather Mao, Yongji Zeng, Jenie Y. Hwang, Joseph R. Burclaff, Shilpa Jain, Jason C. Mills

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Abstract

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.

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代谢调节因子ERRγ控制胃干细胞向分泌胃酸的顶叶细胞分化

顶叶细胞（PC）产生胃酸，以杀死病原体并帮助消化。PC普查失调在疾病中很常见，但PC如何分化尚不清楚。在这里，我们利用小鼠模型和人类胃细胞确定了由峡部干细胞产生的PC祖细胞，并表明它们优先表达细胞代谢调节因子和孤儿核受体雌激素相关受体γ（Esrrg，编码ERRγ）。Esrrg的表达有助于追踪PC分化的分子、细胞和超微结构阶段。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GTP酶。随着祖细胞的成熟，依赖ERRγ的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。我们的工作记录了干细胞在体内单系分化的过程，并建议将ERRγ作为PC相关疾病的治疗靶点。

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来源期刊

Cell stem cell 生物-细胞生物学

CiteScore

37.10

自引率

2.50%

发文量

151

审稿时长

42 days

期刊介绍： Cell Stem Cell is a comprehensive journal covering the entire spectrum of stem cell biology. It encompasses various topics, including embryonic stem cells, pluripotency, germline stem cells, tissue-specific stem cells, differentiation, epigenetics, genomics, cancer stem cells, stem cell niches, disease models, nuclear transfer technology, bioengineering, drug discovery, in vivo imaging, therapeutic applications, regenerative medicine, clinical insights, research policies, ethical considerations, and technical innovations. The journal welcomes studies from any model system providing insights into stem cell biology, with a focus on human stem cells. It publishes research reports of significant importance, along with review and analysis articles covering diverse aspects of stem cell research.