美国贝勒医学院Pavan Reddy团队发现，炎症诱导的表观遗传印记调控肠道干细胞。相关论文于2024年9月3日在线发表在《细胞—干细胞》杂志上。

研究人员在定义明确的急性胃肠道移植物抗宿主病（GI GVHD）临床相关模型中，揭示了炎症对Lgr5⁺ ISC的影响。通过单细胞转录组学、类器官培养、代谢分析、表观基因组学和体内模型，研究人员发现Lgr5⁺ ISC经历了代谢变化，导致琥珀酸积累，从而重编程其表观基因组。

这些变化降低了ISC在体外连续类器官培养和体内连续移植后的分化和再生能力。此外，即使初始炎症暴露得到解决，ISC在体内的再生能力仍然减弱，表明炎症引发的适应不良影响具有持久性。因此，炎症在ISC的表观基因组上留下了印记，这种印记持续存在，并影响其对未来压力或挑战的适应能力。

据介绍，尚不清楚肠道干细胞（ISC）是否以及如何适应炎症暴露，以及这种适应是否会留下影响其后续再生的“痕迹”。

附：英文原文

Title: Inflammation-induced epigenetic imprinting regulates intestinal stem cells

Author: Dongchang Zhao, Visweswaran Ravikumar, Tyler J. Leach, Daniel Kraushaar, Emma Lauder, Lu Li, Yaping Sun, Katherine Oravecz-Wilson, Evan T. Keller, Fengju Chen, Laure Maneix, Robert R. Jenq, Robert Britton, Katherine Y. King, Ana E. Santibanez, Chad J. Creighton, Arvind Rao, Pavan Reddy

Issue&Volume: September 3, 2024

Abstract: It remains unknown whether and how intestinal stem cells (ISCs) adapt to inflammatory exposure and whether the adaptation leaves scars that will affect their subsequent regeneration. We investigated the consequences of inflammation on Lgr5+ ISCs in well-defined clinically relevant models of acute gastrointestinal graft-versus-host disease (GI GVHD). Utilizing single-cell transcriptomics, as well as organoid, metabolic, epigenomic, and in vivo models, we found that Lgr5+ ISCs undergo metabolic changes that lead to the accumulation of succinate, which reprograms their epigenome. These changes reduced the ability of ISCs to differentiate and regenerate ex vivo in serial organoid cultures and also in vivo following serial transplantation. Furthermore, ISCs demonstrated a reduced capacity for in vivo regeneration despite resolution of the initial inflammatory exposure, demonstrating the persistence of the maladaptive impact induced by the inflammatory encounter. Thus, inflammation imprints the epigenome of ISCs in a manner that persists and affects their sensitivity to adapt to future stress or challenges.

DOI: 10.1016/j.stem.2024.08.006

Source: https://www.cell.com/cell-stem-cell/abstract/S1934-5909(24)00292-3