In vivo glycan engineering at the cell-matrix interface to control stem cell fate

 描述(申请人提供)：干细胞具有非凡的能力，可以发育成成人身体的一系列功能细胞类型，可用于修复受损或患病的组织。尽管在实验室实现选择性分化方面取得了进展，但控制干细胞移植后的命运仍然是一个悬而未决的挑战，也是干细胞作为治疗药物使用的一个重大障碍。干细胞在发育过程中的指定是由生长因子等形态因子的协同作用所协调的，这些形态因子启动细胞内信号级联激活基因转录。干细胞表面的多糖在调节生长因子与其同源受体的相互作用中起着关键作用；然而，在实现分化选择性的背景下，它们的调节功能在很大程度上还没有被探索。拟议项目的目标是创造新的技术来操纵干细胞表面的多糖结构，以调整体内细胞-基质界面上内源生长因子的关联。为了实现这一目标，提出了两种截然不同的方法。第一种方法描述了在移植前用对目标生长因子具有亲和力的纳米级拟糖材料对干细胞表面进行预置。一旦重塑的细胞被输送到组织中，这些材料将 促进内源性生长因子的联合，激活信号和分化。第二种方法概述了在体内将这些材料定向输送到干细胞表面，同时抑制这些细胞中的葡聚糖生产。这种原位重塑将允许我们在关键的连接处暂时覆盖天然的多糖信号，以实现生长因子信号的选择性激活和所需的分化结果。这项工作将为再生医学领域的一个关键问题提供新的解决方案，并将为探索多糖丰富的生物学在干细胞技术、组织工程和生物医学中的应用开辟新的机会。

 DESCRIPTION (provided by applicant): Stem cells have the remarkable ability to develop into a range of functional cell types of the adult body that can be used to repair damaged or diseased tissues. Despite advances in achieving selective differentiation in the laboratory, controlling the fate of stem cells post-transplantation still remains an unsolved challenge and a significant obstacle to the use of stem cells as therapeutics. Stem cell specification during development is orchestrated by the concerted action of morphogens, such as growth factors, which initiate intracellular signaling cascades activating gene transcription. Glycans populating surfaces of stem cells play a key role in regulating the interactions of growth factors with their cognate receptors; however, their regulatory functions have been largely unexplored in the context of achieving selectivity in differentiation. The objective of the proposed projects is to create new techniques for manipulating glycan structures at the surface of stem cells to tune the association of endogenous growth factors at the cell-matrix interface in vivo. Two distinct approaches are proposed to achieve this goal. The first approach describes priming of the stem cell surface prior to transplantation with nanoscale glycomimetic materials with affinity for a growth factor of interest. Once the remodeled cells are delivered to a tissue, these materials will promote the association of the endogenous growth factor and activate signaling and differentiation. The second approach outlines the targeted delivery of these materials to the surface of stem cells in vivo concomitant with the inhibition of glycan production in these cells. This in situ remodeling will allow us to temporarily override native glycan signals at a critical junction to achieve selective activation of growth factor signaling and a desired differentiation outcome. This work will provide a novel solution to a key problem in the field of regenerative medicine and will open new opportunities for exploration of the rich biology of glycans for applications in stem cell technologies, tissue engineering and biomedicine.