Role of Notch signaling in cell-fate determination of human mammary stem/progenitor cells.
Role of Notch signaling in cell-fate determination of human mammary stem/progenitor cells.
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DOI：
10.1186/bcr920
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发表时间：
2004
期刊：
影响因子：
--
通讯作者：
Wicha MS
中科院分区：
文献类型：
--
作者：
Dontu G;Jackson KW;McNicholas E;Kawamura MJ;Abdallah WM;Wicha MS
Notch信号传导与细胞命运决定的调节有关，例如成人干细胞的自我更新和祖细胞沿着特定谱系的分化。此外，根据细胞和发育背景，Notch途径充当细胞存活和细胞增殖的调节剂。Notch受体在不同类型的上皮化生性病变和肿瘤性病变中均有异常表达，提示Notch可能是一种原癌基因。脊椎动物Notch 1和Notch 4同源基因参与乳腺的正常发育，这些基因的突变形式与小鼠乳腺肿瘤的发生有关。为了确定Notch信号传导在乳腺细胞命运决定中的作用，我们利用了一种新描述的体外系统，其中乳腺干细胞/祖细胞可以悬浮培养为非粘附的“乳腺球”。使用外源配体激活Notch信号传导，或使用先前表征的Notch信号传导拮抗剂抑制Notch信号传导。利用这个系统，我们证明了Notch信号可以作用于乳腺干细胞，以促进自我更新和早期祖细胞，以促进其增殖，如通过增加10倍的次级乳腺球形成后，Notch激活DSL肽所证明的。除了作用于干细胞之外，Notch信号传导还能够作用于多能祖细胞，促进肌上皮谱系特异性定型和增殖。该途径的刺激也促进三维基质胶培养物中的分支形态发生。这些作用被阻断Notch加工的Notch 4阻断抗体或γ分泌酶抑制剂完全抑制。与Notch信号传导对乳腺干细胞/祖细胞的作用相反，该途径的调节对完全定型、分化的乳腺上皮细胞没有可辨别的作用。这些研究表明，Notch信号传导通过作用于干细胞和祖细胞，影响自我更新和谱系特异性分化，在正常人类乳腺发育中起关键作用。基于这些发现，我们提出异常的Notch信号可能有助于乳腺癌的发生，通过解除正常乳腺干细胞的自我更新。
Notch signaling has been implicated in the regulation of cell-fate decisions such as self-renewal of adult stem cells and differentiation of progenitor cells along a particular lineage. Moreover, depending on the cellular and developmental context, the Notch pathway acts as a regulator of cell survival and cell proliferation. Abnormal expression of Notch receptors has been found in different types of epithelial metaplastic lesions and neoplastic lesions, suggesting that Notch may act as a proto-oncogene. The vertebrate Notch1 and Notch4 homologs are involved in normal development of the mammary gland, and mutated forms of these genes are associated with development of mouse mammary tumors. In order to determine the role of Notch signaling in mammary cell-fate determination, we have utilized a newly described in vitro system in which mammary stem/progenitor cells can be cultured in suspension as nonadherent 'mammospheres'. Notch signaling was activated using exogenous ligands, or was inhibited using previously characterized Notch signaling antagonists. Utilizing this system, we demonstrate that Notch signaling can act on mammary stem cells to promote self-renewal and on early progenitor cells to promote their proliferation, as demonstrated by a 10-fold increase in secondary mammosphere formation upon addition of a Notch-activating DSL peptide. In addition to acting on stem cells, Notch signaling is also able to act on multipotent progenitor cells, facilitating myoepithelial lineage-specific commitment and proliferation. Stimulation of this pathway also promotes branching morphogenesis in three-dimensional Matrigel cultures. These effects are completely inhibited by a Notch4 blocking antibody or a gamma secretase inhibitor that blocks Notch processing. In contrast to the effects of Notch signaling on mammary stem/progenitor cells, modulation of this pathway has no discernable effect on fully committed, differentiated, mammary epithelial cells. These studies suggest that Notch signaling plays a critical role in normal human mammary development by acting on both stem cells and progenitor cells, affecting self-renewal and lineage-specific differentiation. Based on these findings we propose that abnormal Notch signaling may contribute to mammary carcinogenesis by deregulating the self-renewal of normal mammary stem cells.
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影响因子：
10.5
作者：
Dontu, G;Abdallah, WM;Wicha, MS
通讯作者：
Wicha, MS
影响因子：
10.5
作者：
Gudjonsson, T;Villadsen, R;Petersen, OW
通讯作者：
Petersen, OW
影响因子：
64.8
作者：
JARRIAULT, S;BROU, C;ISRAEL, A
通讯作者：
ISRAEL, A
影响因子：
8
作者：
Fitzgerald, K;Harrington, A;Leder, P
通讯作者：
Leder, P
影响因子：
2.7
作者：
Reynolds, BA;Weiss, S
通讯作者：
Weiss, S