Division of Gastroenterology, Boston Children's Hospital, 300 Longwood Avenue, Boston, MA 02115, USA; Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA.
Division of Endocrinology, Boston Children's Hospital, 300 Longwood Avenue, Boston, MA 02115, USA.
Stem Cell Reports. 2018 Jan 9;10(1):17-26. doi: 10.1016/j.stemcr.2017.11.015. Epub 2017 Dec 21.
The intestinal epithelium serves as an essential barrier to the outside world and is maintained by functionally distinct populations of rapidly cycling intestinal stem cells (CBC ISCs) and slowly cycling, reserve ISCs (r-ISCs). Because disruptions in the epithelial barrier can result from pathological activation of the immune system, we sought to investigate the impact of inflammation on ISC behavior during the regenerative response. In a murine model of αCD3 antibody-induced small-intestinal inflammation, r-ISCs proved highly resistant to injury, while CBC ISCs underwent apoptosis. Moreover, r-ISCs were induced to proliferate and functionally contribute to intestinal regeneration. Further analysis revealed that the inflammatory cytokines interferon gamma and tumor necrosis factor alpha led to r-ISC activation in enteroid culture, which could be blocked by the JAK/STAT inhibitor, tofacitinib. These results highlight an important role for r-ISCs in response to acute intestinal inflammation and show that JAK/STAT-1 signaling is required for the r-ISC regenerative response.
肠上皮作为与外界的重要屏障，由功能不同的快速循环肠干细胞（CBC ISCs）和缓慢循环的储备 ISC（r-ISC）维持。因为上皮屏障的破坏可能是免疫系统病理性激活的结果，所以我们试图研究炎症对再生反应过程中 ISC 行为的影响。在抗 αCD3 抗体诱导的小鼠小肠炎症模型中，r-ISC 被证明对损伤具有很强的抵抗力，而 CBC ISC 则发生凋亡。此外，r-ISC 被诱导增殖并对肠道再生起到功能作用。进一步的分析表明，炎症细胞因子干扰素γ和肿瘤坏死因子α在类器官培养中导致 r-ISC 的激活，这种激活可以被 JAK/STAT 抑制剂托法替尼阻断。这些结果突出了 r-ISC 在应对急性肠道炎症中的重要作用，并表明 JAK/STAT-1 信号通路对于 r-ISC 的再生反应是必需的。
