Department of Gastroenterology, Keio University School of Medicine, Tokyo 108-8345, Japan; email:
Annu Rev Cell Dev Biol. 2015;31:269-89. doi: 10.1146/annurev-cellbio-100814-125218. Epub 2015 Oct 2.
In the adult mammalian body, self-renewal of tissue stem cells is regulated by extracellular niche environments in response to the demands of tissue organization. Intestinal stem cells expressing Lgr5 constantly self-renew in their specific niche at the crypt bottom to maintain rapid turnover of the epithelium. Niche-regulated stem cell self-renewal is perturbed in several mouse genetic models and during human tumorigenesis, suggesting roles for EGF, Wnt, BMP/TGF-β, and Notch signaling. In vitro niche reconstitution capitalizing on this knowledge has enabled the growth of single intestinal stem cells into mini-gut epithelial organoids comprising Lgr5(+) stem cells and all types of differentiated lineages. The mini-gut organoid culture platform is applicable to various types of digestive tissue epithelium from multiple species. The mechanism of self-renewal in organoids provides novel insights for organogenesis, regenerative medicine, and tumorigenesis of the digestive system.
在成年哺乳动物体内，组织干细胞的自我更新受细胞外生态位环境的调节，以响应组织的需求。表达 Lgr5 的肠干细胞在隐窝底部的特定生态位中不断自我更新，以维持上皮细胞的快速更替。几种小鼠遗传模型和人类肿瘤发生过程中，受生态位调节的干细胞自我更新受到干扰，提示 EGF、Wnt、BMP/TGF-β 和 Notch 信号的作用。利用这方面的知识进行体外生态位重建，使得单个肠干细胞能够生长成为包含 Lgr5(+)干细胞和所有类型分化谱系的迷你肠道上皮类器官。迷你肠道类器官培养平台适用于来自多种物种的各种类型的消化组织上皮细胞。类器官的自我更新机制为消化系统的器官发生、再生医学和肿瘤发生提供了新的见解。
