Efficient colonic mucosal wound repair requires Trem2 signaling
Efficient colonic mucosal wound repair requires Trem2 signaling
复制标题
DOI：
10.1073/pnas.0803343106
复制
发表时间：
2009-01-06
影响因子：
11.1
通讯作者：
Stappenbeck, Thaddeus S.
中科院分区：
文献类型：
--
作者：
Seno, Hiroshi;Miyoshi, Hiroyuki;Stappenbeck, Thaddeus S.
在Lieberkuhn隐窝中的上皮干细胞的驱动下，结肠上皮衬里经历不断的替换。由于损伤或疾病而丢失的干细胞可以被邻近的经历裂变的隐窝所取代。大量管腔微生物的紧密接近为这种修复过程带来了挑战;必须防止感染，同时必须最大限度地减少免疫系统激活和上皮干细胞遗传损伤。为了了解调节小鼠结肠中隐窝/干细胞替代的因素，我们开发了一种类似于皮肤穿刺活检的体内急性损伤系统。与表皮干细胞相反，结肠上皮祖细胞没有迁移到伤口床上。相反，它们的增殖性扩张仅限于邻近伤口床的隐窝，并延迟到愈合的后期。这种增加的上皮增殖与表达Trem 2的巨噬细胞的浸润以及伤口床中IL-4和IL-13的表达增加一致。有趣的是，Trem 2（-/-）小鼠显示结肠粘膜损伤的缓慢且不完全的伤口愈合。我们发现Trem 2（-/-）小鼠愈合的后一阶段显示上皮细胞增殖减少，IFN-γ和TNF-α表达增加，IL-4和IL-13表达减少，经典巨噬细胞活化标志物增加。这些细胞因子在损伤的WT和Trem 2（-/-）小鼠中的消融表明，它们的表达最终决定了伤口愈合的速率和性质。这些研究表明，Trem 2信号传导是促进结肠伤口愈合的重要途径，其中干细胞替代是必要的。
The colonic epithelial lining undergoes constant replacement, driven by epithelial stem cells in crypts of Lieberkuhn. Stem cells lost because of damage or disease can be replaced by adjacent crypts that undergo fission. The close proximity of an extraordinary number of luminal microbes creates a challenge for this repair process; infection must be prevented while immune system activation and epithelial stem cell genetic damage must be minimized. To understand the factors that modulate crypt/stem cell replacement in the mouse colon, we developed an in vivo acute injury system analogous to punch biopsy of the skin. In contrast to epidermal stem cells, colonic epithelial progenitors did not migrate over the wound bed. Instead, their proliferative expansion was confined to crypts adjacent to wound beds and was delayed to the latter phase of healing. This increased epithelial proliferation was coincident with the infiltration of Trem2 expressing macrophages and increased expression of IL-4 and IL-13 in the wound bed. Interestingly, Trem2(-/-) mice displayed slow and incomplete wound healing of colonic mucosal injuries. We found the latter phase of healing in Trem2(-/-) mice showed a diminished burst of epithelial proliferation, increased expression of IFN-gamma and TNF-alpha, diminished expression of IL-4 and IL-13, and increased markers of classical macrophage activation. Ablation of these cytokines in injured WT and Trem2(-/-) mice demonstrated that their expression ultimately determined the rate and nature of wound healing. These studies show that Trem2 signaling is an important pathway to promote healing of wounds in the colon where stem cell replacement is necessary.