Samsung Biomedical Research Institute, Samsung Medical Center, Seoul, Korea.
Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
Inflamm Bowel Dis. 2021 Apr 15;27(5):667-676. doi: 10.1093/ibd/izaa314.
SAMP1/YitFcsJ (SAMP1) mice spontaneously develop terminal ileitis resembling human Crohn disease. SAMP1 mice have exhibited alteration of epithelial cell lineage distribution and an overall proliferation of the crypt cell population; however, it has not been evaluated whether epithelial differentiation is impaired because of dysfunction of intestinal stem cells (ISCs) or their niche factors.
Using the intestine of SAMP1 mice aged 10 to 14 weeks, morphometric alterations in the crypt-villus architecture, ISCs, crypt cells, and differentiated cells; organoid formation capacity of intestinal crypts; and niche signaling pathways were analyzed and compared with those of age-matched control AKR/J (AKR) mice.
The ileum of SAMP1 mice showed increased depth of intestinal crypts and decreased surface area of the villi compared with those in the ileum of AKR mice. The number of ISCs in the ileal crypts did not differ between SAMP1 and AKR mice; however, the number of Paneth cells decreased and the number of transient amplifying cells increased. The organoid formation rate of the ileal crypts of SAMP1 mice decreased significantly compared with that of AKR mice. The performance of RNA sequencing for intestinal crypts found that the expression of ISC niche factors, such as Wnt3, Dll1, and Dll4, was decreased significantly in the ileal crypts of SAMP1 mice compared with those of AKR mice. Among the ISC niche signals, the Notch signaling-related genes tended to be downregulated. In particular, immunocytochemistry revealed that the expression of Paneth cell-expressing Notch ligand Dll4 was significantly decreased in the intestinal tissue and organoids of SAMP1 mice compared with those of AKR mice.
Depletion of niche factors for ISCs contributes to the alteration of epithelial differentiation in SAMP1 mice.
SAMP1/YitFcsJ（SAMP1）小鼠自发发展为类似于人类克罗恩病的末端回肠炎。SAMP1 小鼠表现出上皮细胞谱系分布的改变和隐窝细胞群体的整体增殖；然而，尚未评估上皮分化是否因肠干细胞（ISCs）或其龛位因子功能障碍而受损。
使用 10 至 14 周龄 SAMP1 小鼠的肠道，分析隐窝-绒毛结构、ISCs、隐窝细胞和分化细胞的形态学改变；肠道隐窝的类器官形成能力；以及龛位信号通路，并与年龄匹配的 AKR/J（AKR）小鼠进行比较。
与 AKR 小鼠相比，SAMP1 小鼠的回肠隐窝深度增加，而绒毛表面积减小。回肠隐窝中的 ISC 数量在 SAMP1 和 AKR 小鼠之间没有差异；然而，Paneth 细胞数量减少，短暂扩增细胞数量增加。SAMP1 小鼠回肠隐窝的类器官形成率与 AKR 小鼠相比显著降低。肠道隐窝 RNA 测序结果表明，SAMP1 小鼠回肠隐窝中 ISC 龛位因子（如 Wnt3、Dll1 和 Dll4）的表达显著降低。在 ISC 龛位信号中，Notch 信号相关基因呈下调趋势。特别是免疫细胞化学显示，SAMP1 小鼠的肠道组织和类器官中表达的 Paneth 细胞表达的 Notch 配体 Dll4 明显减少。
ISCs 龛位因子的耗竭导致 SAMP1 小鼠上皮分化的改变。
