PDGFRα(+) pericryptal stromal cells are the critical source of Wnts and RSPO3 for murine intestinal stem cells in vivo.
PDGFRα(+) pericryptal stromal cells are the critical source of Wnts and RSPO3 for murine intestinal stem cells in vivo.
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DOI：
10.1073/pnas.1713510115
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发表时间：
2018-04-03
影响因子：
11.1
通讯作者：
Virshup DM
中科院分区：
文献类型：
--
作者：
Greicius G;Kabiri Z;Sigmundsson K;Liang C;Bunte R;Singh MK;Virshup DM
体内的组织干细胞存在于高度结构化的小生境中，为增殖和分化提供信号。要了解利基的作用，就需要确定提供这些调节的关键细胞类型。在肠道中，R-Spinins和Wnts是干细胞生态位的重要调节者。在这里，我们鉴定了血小板衍生生长因子受体α谱系的上皮下肌纤维母细胞是分泌这些配体的特定基质细胞类型。这些数据证明了上皮干细胞和潜在的调节基质生态位之间的密切相互作用，并为正常内稳态和损伤后的组织恢复提供了洞察力。WNTS和R-Spinins(RSPO)通过调节隐窝细胞的增殖和分化来维持肠道内环境的稳定。在体外，Paneth细胞在类器官中分泌的WNTs可以调节表达Lgr5的肠道干细胞的增殖和分化。然而，在活体中，Paneth细胞乃至所有上皮性Wnt的产生都是完全可有可无的，维持肠道干细胞生态位的Wnts和RSPO的细胞来源尚不清楚。在这里，我们研究了基质WNTS和RSPO_3在调节肠道内环境稳定中的来源和功能作用。Rsp3在固有层中的肌成纤维细胞中高度表达，在刺激Wnt/β-catenin信号和类器官生长方面比Rsp1强几个数量级。间质Rsp3体外消融导致器官生长明显减少，而外源RSP03蛋白挽救了这一现象。已知的是，血小板衍生生长因子受体α(α)在隐窝周围肌成纤维细胞中表达。因此，我们评估了PDGFRα是否识别了关键的基质细胞。在体内，切除PDGFRα+细胞中的PORCN阻止了肠道隐窝的形成，表明基质中Wnt的产生对于支持肠道干细胞生态位是必要的，也是充分的。切除PDGFRα+细胞中Rspo3的小鼠肠道隐窝Wnt/β-catenin信号转导和潘氏细胞分化减少，在葡聚糖硫酸钠应激下表现出超敏反应。这些数据支持由WNTS和RSPO_3共同调节的肠道干细胞生态位模型，该模型主要由PDGFRα标记的基质肌成纤维细胞提供。
Tissue stem cells in vivo reside in highly structured niches that provide signals for proliferation and differentiation. Understanding the role of the niche requires identifying the key cell types that provide these regulators. In the intestine, R-spondins and Wnts are essential regulators of the stem-cell niche. Here we identify subepithelial myofibroblasts of the PDGF receptor α lineage as the specific stromal cell type that secretes these ligands. These data demonstrate the close interaction between epithelial stem cells and the underlying regulatory stroma niche and provide insights into both normal homeostasis and tissue recovery after injury. Wnts and R-spondins (RSPOs) support intestinal homeostasis by regulating crypt cell proliferation and differentiation. Ex vivo, Wnts secreted by Paneth cells in organoids can regulate the proliferation and differentiation of Lgr5-expressing intestinal stem cells. However, in vivo, Paneth cell and indeed all epithelial Wnt production is completely dispensable, and the cellular source of Wnts and RSPOs that maintain the intestinal stem-cell niche is not known. Here we investigated both the source and the functional role of stromal Wnts and RSPO3 in regulation of intestinal homeostasis. RSPO3 is highly expressed in pericryptal myofibroblasts in the lamina propria and is several orders of magnitude more potent than RSPO1 in stimulating both Wnt/β-catenin signaling and organoid growth. Stromal Rspo3 ablation ex vivo resulted in markedly decreased organoid growth that was rescued by exogenous RSPO3 protein. Pdgf receptor alpha (PdgfRα) is known to be expressed in pericryptal myofibroblasts. We therefore evaluated if PdgfRα identified the key stromal niche cells. In vivo, Porcn excision in PdgfRα+ cells blocked intestinal crypt formation, demonstrating that Wnt production in the stroma is both necessary and sufficient to support the intestinal stem-cell niche. Mice with Rspo3 excision in the PdgfRα+ cells had decreased intestinal crypt Wnt/β-catenin signaling and Paneth cell differentiation and were hypersensitive when stressed with dextran sodium sulfate. The data support a model of the intestinal stem-cell niche regulated by both Wnts and RSPO3 supplied predominantly by stromal pericryptal myofibroblasts marked by PdgfRα.
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影响因子：
10.5
作者：
de Lau W;Peng WC;Gros P;Clevers H
通讯作者：
Clevers H
影响因子：
64.8
作者：
Hao, Huai-Xiang;Xie, Yang;Cong, Feng
通讯作者：
Cong, Feng
影响因子：
29.4
作者：
Farin, Henner F.;Van Es, Johan H.;Clevers, Hans
通讯作者：
Clevers, Hans
DOI：
10.1007/bf02932850
发表时间：
1982-01-01
期刊：
VIRCHOWS ARCHIV B-CELL PATHOLOGY INCLUDING MOLECULAR PATHOLOGY
影响因子：
--
作者：
ALNAFUSSI, AI;WRIGHT, NA
通讯作者：
WRIGHT, NA
影响因子：
64.5
作者：
Festa E;Fretz J;Berry R;Schmidt B;Rodeheffer M;Horowitz M;Horsley V
通讯作者：
Horsley V