Wnt and Notch pathways have interrelated opposing roles on prostate progenitor cell proliferation and differentiation.
Wnt and Notch pathways have interrelated opposing roles on prostate progenitor cell proliferation and differentiation.
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DOI：
10.1002/stem.606
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发表时间：
2011-04
期刊：
影响因子：
5.2
通讯作者：
Spencer, David M.
中科院分区：
文献类型：
--
作者：
Shahi, Payam;Seethammagari, Mamatha R.;Valdez, Joseph M.;Xin, Li;Spencer, David M.
组织干细胞能够自我更新和分化以维持恒定的干细胞群体并在组织内产生多个细胞。Wnt信号传导先前已被确定为维持组织干细胞的关键介质;然而，与成人组织稳态中涉及的其他发育关键信号传导途径（如Notch）的可能交叉调节尚未得到很好的理解。通过使用体外前列腺干细胞集落通过前列腺球（“前列腺球”）形成测定和体内前列腺重建实验，我们证明了对Sca-1+ CD 49 f+基底/干细胞（B/SC）的Wnt途径诱导促进基底上皮区室的扩增，同时“三阳性”细胞显著增加。（细胞角蛋白[CK] 5+，CK 8+，p63+）前列腺祖细胞，伴随着参与细胞周期诱导的已知Wnt靶基因的上调。此外，Wnt诱导影响上皮-间充质转化标记基因的表达，提示引发B/SC充当潜在肿瘤起始细胞的可能机制。有趣的是，B/SC中Wnt信号的诱导导致Notch 1转录物的下调，这与其在前列腺细胞中假定的抗增殖作用一致。相反，前列腺祖细胞中Notch信号传导的诱导抑制其增殖并破坏前列腺球形成。体内前列腺重建测定进一步证明，在B/SC中诱导Notch破坏了表达活化的Notch 1等位基因、Notch-1胞内结构域的细胞中的适当腺泡形成。这些数据强调了Wnt/Notch交叉调节在成体干细胞生物学中的重要性，并表明Wnt信号通过调节Notch信号来控制上皮祖细胞的增殖和/或维持。
Tissue stem cells are capable of both self-renewal and differentiation to maintain a constant stem cell population and give rise to the plurality of cells within a tissue. Wnt signaling has been previously identified as a key mediator for the maintenance of tissue stem cells; however, possible cross-regulation with other developmentally critical signaling pathways involved in adult tissue homeostasis, such as Notch, is not well understood. By using an in vitro prostate stem cell colony (“prostasphere”) formation assay and in vivo prostate reconstitution experiments, we demonstrate that Wnt pathway induction on Sca-1+ CD49f+ basal/stem cells (B/SCs) promotes expansion of the basal epithelial compartment with noticeable increases in “triple positive” (cytokeratin [CK] 5+, CK8+, p63+) prostate progenitor cells, concomitant with upregulation of known Wnt target genes involved in cell-cycle induction. Moreover, Wnt induction affects expression of epithelial-to-mesenchymal transition signature genes, suggesting a possible mechanism for priming B/SC to act as potential tumor-initiating cells. Interestingly, induction of Wnt signaling in B/SCs results in downregulation of Notch1 transcripts, consistent with its postulated antiproliferative role in prostate cells. In contrast, induction of Notch signaling in prostate progenitors inhibits their proliferation and disrupts prostasphere formation. In vivo prostate reconstitution assays further demonstrate that induction of Notch in B/SCs disrupts proper acini formation in cells expressing the activated Notch1 allele, Notch-1 intracellular domain. These data emphasize the importance of Wnt/Notch cross-regulation in adult stem cell biology and suggest that Wnt signaling controls the proliferation and/or maintenance of epithelial progenitors via modulation of Notch signaling.
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DOI：
10.1126/science.1189992
发表时间：
2010-07-30
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Goldstein AS;Huang J;Guo C;Garraway IP;Witte ON
通讯作者：
Witte ON
影响因子：
20.3
作者：
Carlesso, N;Aster, JC;Scadden, DT
通讯作者：
Scadden, DT
影响因子：
11.2
作者：
Pannequin, Julie;Bonnans, Caroline;Hollande, Frederic
通讯作者：
Hollande, Frederic
影响因子：
4.8
作者：
Orr, Brigid;Grace, O. Cathal;Thomson, Axel A.
通讯作者：
Thomson, Axel A.
影响因子：
10.5
作者：
Nguyen, BC;Lefort, K;Dotto, GP
通讯作者：
Dotto, GP