摘要
作为干细胞特异性标志物的富含亮氨酸重复序列的G蛋白偶联受体5(leucine-rich repeat-containing G protein-coupled receptor 5,Lgr5)是细胞膜上的一段七次跨膜受体蛋白,它通过调控Wnt/β-catenin信号维持干细胞增殖与分化平衡,同时与BMP、Notch等通路耦合,协同促进类器官的形成。类器官是一种在体外培养的、具有类似真实器官结构和功能的3D细胞团,不仅能还原组织复杂的结构,也能模拟组织的生理环境,是各种组织器官研究比较精准的体外模型。近年来,类器官为营养吸收、疾病建模、药物筛选和基因编辑等方面的研究提供了比细胞更真实的模型,在生物医学领域引起了广泛关注。因此,本文重点综述了Lgr5通过与R-spondins结合并增强Wnt/β-catenin信号通路,进而调控干细胞自更新与定向分化的分子机制,阐述了其作为核心驱动力在构建微型肠道、肝脏及胰腺类器官中的关键作用,同时,详细探讨了消化道类器官在模拟结直肠癌、非酒精性脂肪肝等疾病病理,以及作为供体组织用于肠黏膜损伤修复和胆管重建等再生医学领域的具体应用,最后,针对目前类器官技术面临的基质胶成分不明确、缺乏血管化和免疫微环境等挑战,提出了结合微流控芯片、合成生物支架及多细胞共培养技术实现类器官复杂化、标准化的未来发展方向,旨在为消化系统疾病的精准治疗提供理论依据。
Leucine-rich repeat-containing G protein-coupled receptor 5(Lgr5)has been identified as a reliable marker for adult stem cells in various tissues.With a transmembrane region consisting of sevenα-helical segments,Lgr5 plays a pivotal role in maintaining the delicate balance between stem cell self-renewal and differentiation.This regulatory function is primarily executed through the potentiation of the Wnt/β-catenin signaling pathway upon binding with its ligands,R-spondins.This article provides a comprehensive review on molecular mechanisms by which Lgr5 modulates stem cell behavior and its indispensable role in the formation of digestive system organoids,including intestine,liver,and pancreas.We first elucidate the synergistic interplay between Lgr5-mediated Wnt signaling and other crucial pathways such as BMP,Notch,and EGF,which collectively create a biomimetic“niche”for organoid development in vitro.This Lgr5-mediated self-organization serves as the biological foundation for constructing three dimensional(3D)organoids,as 3D cell clusters derive from stem cells with structural and functional characteristics that closely mimic native organs.Compared to traditional 2D cell cultures,organoids offer a superior model for studying tissue physiology and complex cell-cell interactions.Furthermore,this review highlights the diverse applications of digestive system organoids in biomedical research.In disease modeling,we discuss how these platforms simulate the pathological progression of colorectal cancer,non-alcoholic fatty liver disease,and hereditary metabolic disorders through CRISPR-Cas9 gene editing and environmental induction.In the field of regenerative medicine,the potential of organoids as transplantable units for repairing intestinal mucosal damage and reconstructing bile duct structures is explored.Despite the significant advancements,critical challenges remain in the current development of organoid technology.We identify several major limitations.First,organoids are highly dependent on animal-derived basement membrane matrix,which has poorly defined components.Second,current models lack functional vascularization.Third,they lack an integrated immune microenvironment.These limitations restrict the translational potential of organoid technology.To address these challenges,we propose future research directions,emphasizing the integration of microfluidic“organ-on-a-chip”systems,synthetic bio-scaffolds,and multi-lineage co-culture techniques.These innovations aim for more complexity and standardization in organoid models,providing a more robust theoretical and technical foundation for personalized medicine and drug discovery for digestive diseases.
作者
姚拓新
李幸
印遇龙
何流琴
YAO Tuoxin;LI Xing;YIN Yulong;HE Liuqin(Hunan Provincial Key Laboratory of Animal Intestinal Function and Regulation,Hunan International Joint Laboratory of Animal Intestinal Ecology and Health,College of Life Sciences,Hunan Normal University,Changsha 410081,Hunan,China;Interdisciplinary Science Center,Institute of Zoology,Chinese Academy of Sciences,Beijing 100101,China;Hunan Provincial Key Laboratory of Animal Nutritional Physiology and Metabolic Process,National Engineering Laboratory for Pollution Control and Waste Utilization in Livestock and Poultry Production,Institute of Subtropical Agriculture,Chinese Academy of Sciences,Changsha 410125,Hunan,China)
出处
《合成生物学》
北大核心
2026年第1期233-245,共13页
Synthetic Biology Journal
基金
国家自然科学基金(U23A20233,32172755,32130099)
湖南省科技创新“领军人才”项目(2023RC1054)
湖南省重大基础研究项目(2024JC0007)。
