Green Center for Systems Biology, Simmons Cancer Center, Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Department of Cellular and Molecular Medicine, University of Arizona Cancer Center, University of Arizona, Tucson, AZ 85724, USA.
Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA 94158, USA.
Dev Cell. 2018 Mar 12;44(5):624-633.e4. doi: 10.1016/j.devcel.2018.01.024. Epub 2018 Mar 1.
The intestinal epithelium maintains a remarkable balance between proliferation and differentiation despite rapid cellular turnover. A central challenge is to elucidate mechanisms required for robust control of tissue renewal. Opposing WNT and BMP signaling is essential in establishing epithelial homeostasis. However, it has been difficult to disentangle contributions from multiple sources of morphogen signals in the tissue. Here, to dissect epithelial-autonomous morphogenic signaling circuits, we developed an enteroid monolayer culture system that recapitulates four key properties of the intestinal epithelium, namely the ability to maintain proliferative and differentiated zones, self-renew, polarize, and generate major intestinal cell types. We systematically perturb intrinsic and extrinsic sources of WNT and BMP signals to reveal a core morphogenic circuit that controls proliferation, tissue organization, and cell fate. Our work demonstrates the ability of intestinal epithelium, even in the absence of 3D tissue architecture, to control its own growth and organization through morphogen-mediated feedback.
尽管肠道上皮细胞的细胞更替速度很快，但它仍能维持惊人的增殖和分化平衡。一个主要的挑战是阐明组织更新的强大控制所需的机制。相反的 WNT 和 BMP 信号在建立上皮细胞稳态中是必不可少的。然而，要理清组织中多种形态发生信号源的贡献一直很困难。在这里，为了剖析上皮细胞自主的形态发生信号回路，我们开发了一种类器官单层培养系统，该系统再现了肠道上皮的四个关键特性，即维持增殖和分化区、自我更新、极化和产生主要肠道细胞类型的能力。我们系统地扰动内在和外在的 WNT 和 BMP 信号源，揭示了一个控制增殖、组织组织和细胞命运的核心形态发生回路。我们的工作表明，即使在没有 3D 组织结构的情况下，肠道上皮也能够通过形态发生介导的反馈来控制自身的生长和组织。
