Non-canonical Wnt signaling and lymphostromal interactions: the role of Wnt4/Frizzled6 axis in early immune development

成人免疫系统的所有细胞都来源于少量的骨髓造血干细胞（HSC），这些造血干细胞存在于专门的口袋或壁龛中，周围环绕着被认为调节HSC功能的其他细胞。除了能够发育成不同的血细胞谱系外，HSC还具有独特的自我更新能力。它们罕见的细胞分裂是不对称的，导致产生一个与母细胞相同的子HSC和一个失去几个干细胞特征的祖细胞。这种自我更新依赖于HSC-生态位相互作用，并且对于循环血细胞的连续生成至关重要。该领域最大的技术挑战之一是开发培养HSC扩增的方法，同时限制其自我更新能力的丧失。 我对Wnt家族信号蛋白调控HSC-生态位相互作用感兴趣。特别是，我最近的研究结果已经确定了一个非传统的信号通路，参与调节小鼠骨髓中的HSC数量。其中一种分子是细胞表面受体蛋白Frizzled 6。已知该途径调节皮肤中的细胞取向和细胞-细胞相互作用。我建议，同样的信号也可以参与造血干细胞与骨髓龛细胞的相互作用，并控制造血干细胞在龛内的方向，从而影响他们的自我更新。 目前的研究计划集中在Frizzled 6对HSC-生态位相互作用的影响，HSC在生态位内的方向，以及细胞内其他相关蛋白的定位。总之，这里提出的工作将提高我们的理解机制，调节造血干细胞在骨髓中的定位。此外，这些研究将导致识别用于培养中HSC扩增的新型生长因子和小鼠模型的开发，以促进对非传统Wnt信号传导的进一步研究。

All cells of the adult immune system are derived from a small number of bone marrow hematopoietic stem cells (HSC) that are found in specialized pockets or niches, surrounded by other cells that are believed to regulate HSC function. In addition to being able to develop into the different blood cell lineages, HSC also have the unique ability to self-renew. Their infrequent cell divisions are asymmetrical, resulting in the generation of one daughter HSC, identical to the mother cell, and one progenitor cell that has lost several stem cell characteristics. This self-renewal is dependent on HSC-niche interactions and is essential for the continuous generation of circulating blood cells. One of the greatest technical challenges in the field is to develop methods for HSC expansion in culture while limiting the loss of their self-renewal capacity. I am interested in the regulation of HSC-niche interactions by the Wnt-family of signaling proteins. In particular, my recent results have identified a non-traditional signaling pathway that is involved in the regulation of HSC numbers in mouse bone marrow. One of the molecules involved is the cell surface receptor protein Frizzled6. The pathway is known to regulate cellular orientation and cell-cell interaction in the skin. I propose that the same signals could also be involved in the interaction of HSC with the bone marrow niche cells and control the orientation of HSC inside the niche, thus influencing their self-renewal. The current research proposal focuses on the influence of Frizzled6 on HSC-niche interactions, HSC orientation inside the niche, and the localization of other associated proteins inside the cell. Together the work proposed here will improve our understanding of the mechanisms that regulate HSC localization in the bone marrow. Furthermore, these studies should lead to the identification of novel growth factors for HSC expansion in culture and the development of mouse models to facilitate further research on non-traditional Wnt signaling.