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: 2022
• 资助国家: 加拿大
• 起止时间: 2022-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=757475
• 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源自少量骨髓造血干细胞 (HSC)，这些细胞存在于专门的口袋或壁龛中，周围环绕着其他据信可调节 HSC 功能的细胞。造血干细胞除了能够发育成不同的血细胞谱系外，还具有独特的自我更新能力。它们不频繁的细胞分裂是不对称的，导致产生一种与母细胞相同的子代HSC，以及一种失去了多种干细胞特征的祖细胞。这种自我更新依赖于 HSC-生态位的相互作用，对于循环血细胞的持续生成至关重要。该领域最大的技术挑战之一是开发 HSC 在培养物中扩增的方法，同时限制其自我更新能力的丧失。我们相信，更好地了解生态位环境将有助于确定更好的培养条件。Wnt 信号蛋白家族对 HSC 生态位相互作用的调节是我实验室的主要主题之一。特别是，我最近的研究结果发现了一条非传统信号通路参与小鼠骨髓中 HSC 数量的调节。所涉及的分子之一是细胞表面受体蛋白 Frizzled6，我们最近的工作将其确定为压力下 HSC 功能的重要调节因子。已知该途径可调节皮肤中的细胞方向和细胞间相互作用。我们认为相同的信号也可能参与造血干细胞与骨髓微环境细胞的相互作用，并控制微环境内造血干细胞的方向，从而影响它们的自我更新。因此，我们的长期目标是确定参与 HSC-生态位相互作用的关键膜相关 Wnt 信号分子，并可用于维持培养中的 HSC。当前的研究计划重点关注 Frizzled6 影响 HSC 的机制-生态位相互作用、生态位内的 HSC 方向以及细胞内其他相关蛋白的定位。我们还将评估另一种已知与其他细胞类型中的 Frizzled6 相互作用和协作的表面蛋白的作用。这里提出的工作将共同提高我们对调节造血干细胞在骨髓中定位的机制的理解。此外，这些研究应该能够鉴定出用于 HSC 培养扩增的新型生长因子，并开发小鼠模型，以促进对非传统 Wnt 信号传导的进一步研究。