Canonical Wnt signals combined with suppressed TGFβ/BMP pathways promote renewal of the native human colonic epithelium.
Canonical Wnt signals combined with suppressed TGFβ/BMP pathways promote renewal of the native human colonic epithelium.
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DOI：
10.1136/gutjnl-2012-304067
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发表时间：
2014-04
期刊：
影响因子：
24.5
通讯作者：
Williams MR
中科院分区：
文献类型：
--
作者：
Reynolds A;Wharton N;Parris A;Mitchell E;Sobolewski A;Kam C;Bigwood L;El Hadi A;Münsterberg A;Lewis M;Speakman C;Stebbings W;Wharton R;Sargen K;Tighe R;Jamieson C;Hernon J;Kapur S;Oue N;Yasui W;Williams MR
人类肠上皮的一个决定性特征是它是体内更新最快的组织。然而，事实证明，在人类肠道中研究组织更新的过程以及控制其协调的机制是困难的。研究天然人结肠上皮中经典 Wnt 和 TGFβ/骨形态发生蛋白 (BMP) 通路对干细胞驱动的组织更新的调节。从粘膜组织样本中分离出完整的人类结肠隐窝，并将其置于针对稳态组织更新而优化的 3D 培养条件中。高亲和力 mRNA 原位杂交和免疫组织化学得到功能基因组和生物成像技术的补充。确定信号通路调节剂对肠干细胞生物学状态、隐窝细胞增殖、迁移、分化和脱落的影响。天然人类结肠隐窝表现出典型 Wnt、TGFβ 和 BMP 通路的独特激活特征。一群肠道 LGR5/OLFM4 阳性干/祖细胞散布在隐窝基底内的杯状细胞之间。外源性和隐窝细胞自主的经典 Wnt 信号支持稳态肠干/祖细胞增殖，并被 TGFβ 或 BMP 通路激活所拮抗。 Wnt 刺激减少会阻碍隐窝细胞增殖，但隐窝细胞迁移和从隐窝表面脱落不受影响，并导致隐窝减少。天然人类结肠上皮的稳态组织更新依赖于经典 Wnt 信号与受抑制的 TGFβ/BMP 通路的结合。干/祖细胞增殖与隐窝细胞迁移和脱落无关，并且需要不断补充隐窝细胞群。
A defining characteristic of the human intestinal epithelium is that it is the most rapidly renewing tissue in the body. However, the processes underlying tissue renewal and the mechanisms that govern their coordination have proved difficult to study in the human gut. To investigate the regulation of stem cell-driven tissue renewal by canonical Wnt and TGFβ/bone morphogenetic protein (BMP) pathways in the native human colonic epithelium. Intact human colonic crypts were isolated from mucosal tissue samples and placed into 3D culture conditions optimised for steady-state tissue renewal. High affinity mRNA in situ hybridisation and immunohistochemistry were complemented by functional genomic and bioimaging techniques. The effects of signalling pathway modulators on the status of intestinal stem cell biology, crypt cell proliferation, migration, differentiation and shedding were determined. Native human colonic crypts exhibited distinct activation profiles for canonical Wnt, TGFβ and BMP pathways. A population of intestinal LGR5/OLFM4-positive stem/progenitor cells were interspersed between goblet-like cells within the crypt-base. Exogenous and crypt cell-autonomous canonical Wnt signals supported homeostatic intestinal stem/progenitor cell proliferation and were antagonised by TGFβ or BMP pathway activation. Reduced Wnt stimulation impeded crypt cell proliferation, but crypt cell migration and shedding from the crypt surface were unaffected and resulted in diminished crypts. Steady-state tissue renewal in the native human colonic epithelium is dependent on canonical Wnt signals combined with suppressed TGFβ/BMP pathways. Stem/progenitor cell proliferation is uncoupled from crypt cell migration and shedding, and is required to constantly replenish the crypt cell population.
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影响因子：
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作者：
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通讯作者：
Aaltonen, LA
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Lum, Lawrence
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