Piezo1 regulates colon stem cells to maintain epithelial homeostasis through SCD1-Wnt-β-catenin and programming fatty acid metabolism.

IF 6.9 1区生物学 Q1 CELL BIOLOGY Cell reports Pub Date : 2025-03-25 Epub Date: 2025-03-12 DOI:10.1016/j.celrep.2025.115400

Feifei Fang, Gangping Li, Xueyan Li, Jiandi Wu, Ying Liu, Haoren Xin, Zhe Wang, Jianhua Fang, Yudong Jiang, Wei Qian, Xiaohua Hou, Jun Song

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Abstract

Piezo1, which maintains the integrity and function of the intestinal epithelial barrier, is essential for colonic epithelial homeostasis. However, whether and how Piezo1 regulates colon stem cell fate remains unclear. Here, we show that Piezo1 inhibition promotes colon stem cell proliferation. Mechanistically, stearoyl-CoA 9-desaturase 1 (SCD1) is downstream of Piezo1 to affect colon stem cell stemness by acting on the Wnt-β-catenin pathway. For mice, the altered colon stem cell stemness after Piezo1 knockdown and activation was accompanied by a reprogrammed fatty acid (FA) metabolism in colon crypts. Notably, we found that GsMTX4 protects injured colon stem cell stemness in mouse and human colitis organoids. Our results elucidated the role of Piezo1 in regulating normal and postinjury colon stem cell fates through SCD1-Wnt-β-catenin and the SCD1-mediated FA desaturation process. These results provide fresh perspectives on the mechanical factors regulating colon stem cell fate and therapeutic strategies for related intestinal diseases.

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Piezo1通过SCD1-Wnt-β-catenin和编程脂肪酸代谢调节结肠干细胞维持上皮稳态。

Piezo1维持肠上皮屏障的完整性和功能，对结肠上皮稳态至关重要。然而，Piezo1是否以及如何调节结肠干细胞的命运仍不清楚。在这里，我们发现Piezo1抑制促进结肠干细胞增殖。在机制上，硬脂酰辅酶a 9-去饱和酶1 （SCD1）是Piezo1的下游，通过作用于Wnt-β-catenin通路影响结肠干细胞的干性。在小鼠实验中，Piezo1基因敲除和激活后，结肠干细胞的干性发生改变，并伴随着结肠隐窝中脂肪酸（FA）代谢的重编程。值得注意的是，我们发现GsMTX4可以保护小鼠和人类结肠炎类器官中受损的结肠干细胞的干细胞性。我们的研究结果阐明了Piezo1通过SCD1-Wnt-β-catenin和scd1介导的FA去饱和过程调节正常和损伤后结肠干细胞命运的作用。这些结果为研究调节结肠干细胞命运的机械因素和相关肠道疾病的治疗策略提供了新的视角。

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来源期刊

Cell reports CELL BIOLOGY-

CiteScore

13.80

自引率

1.10%

发文量

1305

审稿时长

77 days

期刊介绍： Cell Reports publishes high-quality research across the life sciences and focuses on new biological insight as its primary criterion for publication. The journal offers three primary article types: Reports, which are shorter single-point articles, research articles, which are longer and provide deeper mechanistic insights, and resources, which highlight significant technical advances or major informational datasets that contribute to biological advances. Reviews covering recent literature in emerging and active fields are also accepted. The Cell Reports Portfolio includes gold open-access journals that cover life, medical, and physical sciences, and its mission is to make cutting-edge research and methodologies available to a wide readership. The journal's professional in-house editors work closely with authors, reviewers, and the scientific advisory board, which consists of current and future leaders in their respective fields. The advisory board guides the scope, content, and quality of the journal, but editorial decisions are independently made by the in-house scientific editors of Cell Reports.