The Wnt agonist R-spondin1 regulates systemic graft-versus-host disease by protecting intestinal stem cells.
The Wnt agonist R-spondin1 regulates systemic graft-versus-host disease by protecting intestinal stem cells.
复制标题
DOI：
10.1084/jem.20101559
复制
发表时间：
2011-02-14
期刊：
影响因子：
--
通讯作者：
Teshima T
中科院分区：
文献类型：
--
作者：
Takashima S;Kadowaki M;Aoyama K;Koyama M;Oshima T;Tomizuka K;Akashi K;Teshima T
R-spondin 1通过Wnt信号通路刺激肠干细胞增殖，并防止移植物抗宿主病。移植物抗宿主病（GVHD）是异基因骨髓移植（BMT）的主要并发症，胃肠道（GI）损伤在全身性疾病的扩大中起着关键作用。肠干细胞（ISCs）不仅在生理性组织更新中起关键作用，而且在肠上皮损伤后的再生中也起关键作用。在这项研究中，我们发现移植前预处理方案损害了ISCs;然而，ISCs迅速恢复并恢复了肠道的正常结构。ISCs是GVHD的靶细胞，随着GVHD的发展，ISCs的恢复过程受到明显抑制。注射Wnt激动剂R-spondin 1（R-Spo 1）可保护ISC损伤，增强受损肠上皮的恢复，并抑制随后的炎症细胞因子级联反应。R-Spo 1通过依赖于条件诱导的胃肠道损伤修复的机制改善异基因骨髓移植后的系统性GVHD。我们的研究结果首次表明，ISC损伤在放大系统性GVHD中起着核心作用;因此，我们提出R-Spo 1对ISC的保护作为改善同种异体BMT结果的一种新策略。
R-spondin1 stimulates the proliferation of intestinal stem cells through the Wnt signaling pathway and protects against graft-versus-host disease. Graft-versus-host disease (GVHD) is a major complication of allogeneic bone marrow transplantation (BMT), and damage to the gastrointestinal (GI) tract plays a critical role in amplifying systemic disease. Intestinal stem cells (ISCs) play a pivotal role not only in physiological tissue renewal but also in regeneration of the intestinal epithelium after injury. In this study, we have discovered that pretransplant conditioning regimen damaged ISCs; however, the ISCs rapidly recovered and restored the normal architecture of the intestine. ISCs are targets of GVHD, and this process of ISC recovery was markedly inhibited with the development of GVHD. Injection of Wnt agonist R-spondin1 (R-Spo1) protected against ISC damage, enhanced restoration of injured intestinal epithelium, and inhibited subsequent inflammatory cytokine cascades. R-Spo1 ameliorated systemic GVHD after allogeneic BMT by a mechanism dependent on repair of conditioning-induced GI tract injury. Our results demonstrate for the first time that ISC damage plays a central role in amplifying systemic GVHD; therefore, we propose ISC protection by R-Spo1 as a novel strategy to improve the outcome of allogeneic BMT.
登录
查看更多内容
影响因子：
20.3
作者：
Panoskaltsis-Mortari, A;Lacey, DL;Blazar, BR
通讯作者：
Blazar, BR
影响因子：
20.3
作者：
Blazar, Bruce R.;Weisdorf, Daniel J.;Ferrara, James L. M.
通讯作者：
Ferrara, James L. M.
影响因子：
4.3
作者：
Kim, KA;Zhao, JS;Funk, WD
通讯作者：
Funk, WD
影响因子：
20.3
作者：
Kahl, Christoph;Storer, Barry E.;Storb, Rainer
通讯作者：
Storb, Rainer
影响因子：
64.8
作者：
Reya, T;Clevers, H
通讯作者：
Clevers, H