Article Title: Integration of Notch and Wnt signaling in hematopoietic stem cell maintenance
Authors: Duncan, AW;Rattis, FM;DiMascio, LN;Congdon, KL;Pazianos, G;Zhao, C;Yoon, K;Cook, JM;Willert, K;Gaiano, N;Reya, T
Journal: NAT IMMUNOL
Volume: 6 (3)
Q： Why do you think your paper is highly cited?
A：Stem cells are unique because they have the ability to balance self-renewal with commitment; however, the signals that control this are not fully understood. I think this paper is highly cited because we show how distinct signals interact to control stem cell maintenance. Specifically we show that Notch signaling is highly active in hematopoietic stem cells (HSCs), and is critical for maintaining their undifferentiated state. In contrast, Wnt signaling appears to predominantly control proliferation and survival of HSCs. These data suggest that Notch signaling acts as a switch between renewal and commitment, and provide a model for how Notch and Wnt may be integrated by HSCs to maintain the stem cell state.
Q：Does it describe a new discovery or a new methodology that's useful to others?
A：This work describes a discovery about the mechanisms that control stem cell function. While self-renewal is now beginning to be understood at a molecular level, what remains unclear is how its individual elements (i.e., proliferation and inhibition of differentiation) are regulated. Our work suggests that these two events can be uncoupled and that Notch and Wnt play complementary roles in stem cell maintenance.
Q：Could you summarize the significance of your paper in layman's terms?
A：Because most mature blood stem cells have a limited lifespan, the ability of HSCs to perpetuate themselves through self-renewal and generate new blood cells through commitment is critical to sustaining life. Our work shows that the balance between HSC self-renewal and commitment is regulated by Notch signaling, and that HSC growth and survival are regulated by Wnt signaling. Progress in the basic understanding of regulation of HSC self-renewal has significant practical ramifications, since identification of factors that influence HSC growth is a critical step towards defining ways to expand stem cells in vitro, thereby improving transplantation-based therapies for leukemias and other cancers.
Q： How did you become involved in this research?
A：In our effort to understand how Wnt signaling exerts its influence on HSCs, we discovered that some transcriptional targets of the Notch pathway were upregulated by Wnt signaling. This got us interested in understanding how Notch and Wnt signaling may be linked in the context of stem cell maintenance. As we followed the Notch pathway to determine how it influenced HSCs, we found that inhibiting the pathway led to increased commitment. This made a prediction that Notch signaling should be active in stem cells and mostly inactive during commitment. Fortunately around this time, we found out that Nick Gaiano at Johns Hopkins had generated a Notch reporter mouse. We set up in collaboration with him and this allowed us to show that Notch signaling was in fact highly enriched in stem cells, and was rapidly shut off as stem cells differentiated. We then went on to define the relative roles of Notch and Wnt signaling in this context and found that Wnt signaling was dominant in influencing growth and survival, and Notch signaling was essential for maintaining the undifferentiated state.
Tannishtha Reya, Ph.D.
Assistant Professor
Department of Pharmacology and Cancer Biology
Duke University Medical Center
Durham, NC, USA
领域：免疫学
题目：Notch与Wnt在造血干细胞维持方面信号传导的合作
Q：你认为你的论文为什么会达到高度引用呢？
A：干细胞是很独特的，因为它们有能力定向平衡自我更新；然而，控制这个过程的信号还没有完全搞清楚。我认为这篇论文得到高度引用是因为我们阐明了独特的信号之间的相互作用是如何控制干细胞的维持的。明确的讲我们展示了Notch信号在造血干细胞是高度有活性的，而且对于维持它们的分化状态是很关键的。相反，Wnt信号在控制造血干细胞的增殖和生存方面起主导作用。这些论据暗示了Notch信号象一个开关一样在自我更新和约束自我更新方面，而且为Notch和通过造血干细胞是如何综合起来维持干细胞状态提供了一个模型。
Q：那对于其他研究，该文章是否描述了一个新的发现或新的方法学呢？
A：这个试验工作描述了一个发现，那就是控制干细胞功能机制。人们刚刚开始在分子水平了解自我更新，我们依旧未知的是它的单独的原理（比如分化的增殖和抑制）是如何调控的。我们的试验暗示了这两个事件是分开的，而且Notch与Wnt在干细胞维持方面起了互补的作用。
Q：你能站在一个外行的角度来简要说明一下你的论文的重要意义吗？
A：由于大多数成熟的造血干细胞都有一个有限的生命期，造血干细胞通过自我更新来产生定向的血细胞来维持自己的生存，这种能力对于维持它们的生命很重要。我们的试验表明造血干细胞在平衡自我更新和约束这种更新是受Notch信号所调控的，造血干细胞的生长和生存是受Wnt信号调控的。我们在调控造血干细胞自我更新的基本理解上所取得的进步有着重要的实际结果，因为确定出影响造血干细胞生长的因子对于在体外扩增干细胞、以此改善白血病和其他癌症的移植治疗是一个很重要的步骤。
Q：你是怎样开始这个研究的呢？
A：我们在努力弄明白Wnt信号是怎样影响造血干细胞的时候，我们发现一些Notch通路的转录结果因Wnt信号被上调了。这个使我们对Notch和Wnt信号在干细胞维持的背景下如何联系产生了兴趣。因为我们沿着Notch通路来决定它是如何影响造血干细胞的，我们发现抑制该通路会导致增加定向。这样就有一个预测是，Notch信号在干细胞中应该是有活性的，而在定向的过程中是几乎没有活性的。幸运的是，就在这段时间，我们发现Nick Gaiano at Johns Hopkins产生了一个Notch老鼠。我们和他进行了合作，这就让我们表明了Notch信号事实上在干细胞中是很多见的，而一旦干细胞开始分化它就会中断了。我们之后详细的说明了Notch和Wnt信号通路在这种背景下的相对功能，而且发现Wnt信号通路在影响生长和生存方面是起主导作用的，而Notch信号对于维持未分化状态是必不可少的。
编辑：西门吹血
