Non-canonical Wnt signaling and lymphostromal interactions: impact of Frizzled6/Vangl2 on stem/progenitor cell function

非经典 Wnt 信号传导和淋巴基质相互作用：Frizzled6/Vangl2 对干细胞/祖细胞功能的影响

• 批准号: RGPIN-2018-05258
• 负责人: Heinonen, Krista
• 金额: $ 3.64万
• 依托单位: Institut national de la recherche scientifique
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2020
• 资助国家: 加拿大
• 起止时间: 2020-01-01 至 2021-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=711014
• 关键词: Non; canonical; Wnt; signaling; lymphostromal

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. We believe that a better understanding of the niche environment would help identify better culture conditions. Regulation of HSCniche interactions by the Wnt-family of signaling proteins is one of the main overarching themes in my laboratory. 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 that our recent work identifies as an essential regulator of HSC function under stress. The pathway is known to regulate cellular orientation and cell-cell interaction in the skin. We propose that the same signals could also be involved in the interaction of HSCs with the bone marrow niche cells and control the orientation of HSCs inside the niche, thus influencing their self-renewal. Our long-term goal, therefore, is to identify the key membrane-associated Wnt signaling molecules involved in HSC-niche interactions and that could be used for maintaining HSCs in culture. The current research proposal focuses on the mechanisms by which Frizzled6 could influence HSC-niche interactions, HSC orientation inside the niche, and the localization of other associated proteins inside the cell. We will also evaluate the role of another surface protein known to interact and collaborate with Frizzled6 in other cell types. 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.

成人免疫系统的所有细胞均来自少数骨髓造血干细胞（HSC），这些干细胞（HSC）被发现在专门的口袋或壁ches中，被认为可以调节HSC功能的其他细胞包围。除了能够发展为不同的血细胞谱系外，HSC还具有独特的自我更新能力。它们的细胞分裂不对称是不对称的，导致一个女儿HSC产生与母细胞相同的女儿HSC，并且一个遗传了几个干细胞特征的祖细胞。这种自我更新取决于HSC-niche相互作用，对于连续产生循环血细胞至关重要。该领域最大的技术挑战之一是开发文化中HSC扩展的方法，同时限制其自我更新能力的丧失。我们认为，更好地了解利基环境将有助于确定更好的文化条件。 通过信号蛋白的WNT家庭对HSCNICHE相互作用的调节是我实验室中的主要总体主题之一。特别是，我最近的结果已经确定了与小鼠骨髓中HSC数量调节有关的非传统信号通路。所涉及的分子之一是细胞表面受体蛋白毛躁6，我们最近的工作将其视为应力下HSC功能的必不可少的调节剂。已知该途径调节皮肤中的细胞方向和细胞 - 细胞相互作用。我们提出，同一信号也可能与HSC与骨髓细胞的相互作用有关，并控制利基内部HSC的方向，从而影响其自我更新。因此，我们的长期目标是确定与HSC-niche相互作用有关的关键膜相关的Wnt信号分子，并且可以用于维持培养物中的HSC。 当前的研究建议着重于毛躁6可以影响HSC-NICHE相互作用，HSC方向以及细胞内其他相关蛋白的定位的机制。我们还将评估另一种表面蛋白质的作用，该表面蛋白已知可以与其他细胞类型中的Frizzled6相互作用和合作。这里提出的工作将共同提高我们对调节骨髓中HSC定位机制的理解。此外，这些研究应导致识别培养物中HSC扩展的新生长因子和小鼠模型的发展，以促进对非传统WNT信号传导的进一步研究。