Type 2 Fibroblast Growth Factor Receptor Signaling Preserves Stemness and Prevents Differentiation of Prostate Stem Cells from the Basal Compartment
Type 2 Fibroblast Growth Factor Receptor Signaling Preserves Stemness and Prevents Differentiation of Prostate Stem Cells from the Basal Compartment
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2 型成纤维细胞生长因子受体信号转导保留干性并防止前列腺干细胞从基底室分化
DOI：
10.1074/jbc.m115.661066
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发表时间：
2015-07-17
影响因子：
4.8
通讯作者：
Wang, Fen
中科院分区：
文献类型：
--
作者：
Huang, Yanqing;Hamana, Tomoaki;Wang, Fen
前列腺干细胞（P-SC）能够产生前列腺上皮细胞的所有三个谱系，其包括基底细胞、管腔细胞和神经内分泌细胞。基于前列腺球或类器官培养、细胞谱系追踪、肾包膜植入以及管腔和基底细胞特异性蛋白的表达，已经在人类和小鼠成年前列腺中鉴定出两种类型的P-SC。形成球体的P-SC来自表达P63的基底细胞区室，因此被称为基底P-SC（P-bSC）。管腔P-SC（P-lSC）表达管腔细胞角蛋白和Nkx 3.1。在本文中，我们报告了2型FGF受体（FGFR2）信号传导轴对于保持干细胞和防止P-bSCs分化至关重要。由FGFR底物2 α（FRS2 α）介导的FGFR 2信号传导对于衍生自P63（+）P-bSC的前列腺球的形成和维持是必不可少的。体外P63（+）细胞中Fgfr 2的消融引起前列腺球的崩解。体内Fgfr 2的消融减少了表达P63的基底细胞的数量并富集了管腔细胞。这表明基底干细胞向管腔细胞分化。此外，P63（+）细胞中Fgfr 2的消融导致前列腺的出生后发育缺陷。因此，数据表明FGFR 2信号传导对于保持干细胞性和防止P-bSC分化至关重要。
Prostate stem cells (P-SCs) are capable of giving rise to all three lineages of prostate epithelial cells, which include basal, luminal, and neuroendocrine cells. Two types of P-SCs have been identified in both human and mouse adult prostates based on prostasphere or organoid cultures, cell lineage tracing, renal capsule implantation, and expression of luminal-and basal-specific proteins. The sphere-forming P-SCs are from the basal cell compartment that express P63, and are therefore designated as basal P-SCs (P-bSCs). Luminal P-SCs (P-lSCs) express luminal cytokeratins and Nkx3.1. Herein, we report that the type 2 FGF receptor (FGFR2) signaling axis is crucial for preserving stemness and preventing differentiation of P-bSCs. FGFR2 signaling mediated by FGFR substrate 2 alpha (FRS2 alpha) is indispensable for formation and maintenance of prostaspheres derived from P63(+) P-bSCs. Ablation of Fgfr2 in P63(+) cells in vitro causes the disintegration of prostaspheres. Ablation of Fgfr2 in vivo reduces the number of P63-expressing basal cells and enriches luminal cells. This suggests a basal stem cell-to-luminal cell differentiation. In addition, ablation of Fgfr2 in P63(+) cells causes defective postnatal development of the prostate. Therefore, the data indicate that FGFR2 signaling is critical for preserving stemness and preventing differentiation of P-bSCs.