Molecular Oncology Programme, Growth Factors, Nutrients and Cancer Group, Centro Nacional Investigaciones Oncológicas, Madrid, Spain.
Department of Pathology, Hospital Universitario Ramón y Cajal, Instituto Ramón y Cajal de Investigación Sanitaria, Madrid, Spain.
J Exp Med. 2022 Nov 7;219(11). doi: 10.1084/jem.20212405. Epub 2022 Sep 13.
Intestinal epithelium regenerates rapidly through proliferation of intestinal stem cells (ISCs), orchestrated by potent mitogens secreted within the crypt niche. However, mechanisms regulating these mitogenic factors remain largely unknown. Here, we demonstrate that transit-amplifying (TA) cells, marked by unconventional prefoldin RPB5 interactor (URI), control R-spondin production to guide ISC proliferation. Genetic intestinal URI ablation in mice injures TA cells, reducing their survival capacity, leading to an inflamed tissue and subsequently decreasing R-spondin levels, thereby causing ISC quiescence and disruption of intestinal structure. R-spondin supplementation or restoration of R-spondin levels via cell death inhibition by c-MYC elimination or the suppression of inflammation reinstates ISC proliferation in URI-depleted mice. However, selective c-MYC and p53 suppression are required to fully restore TA cell survival and differentiation capacity and preserve complete intestinal architecture. Our data reveal an unexpected role of TA cells, which represent a signaling platform instrumental for controlling inflammatory cues and R-spondin production, essential for maintaining ISC proliferation and tissue regeneration.
肠上皮通过肠干细胞（ISCs）的增殖迅速再生，这一过程受到隐窝龛内分泌的强效有丝分裂原的调控。然而，调节这些有丝分裂原的机制在很大程度上仍然未知。在这里，我们证明了由非常规前折叠蛋白 RPB5 相互作用蛋白（URI）标记的过渡扩增（TA）细胞控制 R 分泌蛋白的产生，以指导 ISC 的增殖。在小鼠中进行遗传的肠道 URI 缺失会损伤 TA 细胞，降低其存活能力，导致组织炎症，随后降低 R 分泌蛋白水平，从而导致 ISC 静止和肠道结构破坏。通过抑制细胞死亡（如通过消除 c-MYC 或抑制炎症）来补充 R 分泌蛋白或恢复 R 分泌蛋白水平，可以在 URI 缺失的小鼠中恢复 ISC 的增殖。然而，选择性抑制 c-MYC 和 p53 是完全恢复 TA 细胞存活和分化能力并保持完整肠道结构所必需的。我们的数据揭示了 TA 细胞的一个意外作用，即 TA 细胞代表了一个信号平台，对于控制炎症信号和 R 分泌蛋白的产生至关重要，这对于维持 ISC 的增殖和组织再生是必需的。
