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

细胞-基质界面的体内聚糖工程控制干细胞命运

• 批准号: 8955575
• 负责人: Kamil Godula
• 金额: $ 232.5万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-30 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8955575
• 关键词: Adult; Affinity; Biology; Cell surface; Cells; Development; Engineering; Genetic Transcription; Goals; Growth Factor; Growth Factor Interaction; In Situ; Laboratories; Medicine; Outcome; Play; Polysaccharides; Production; Regenerative Medicine; Signal Transduction; Solutions; Stem cells; Structure; Surface; Techniques; Therapeutic; Tissue Engineering; Tissues; Transplantation; Work; cell type; in vivo; interest; morphogens; nanoscale; novel; public health relevance; receptor; repaired; stem cell fate; stem cell fate specification; stem cell technology; stem cell therapy; targeted delivery

 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.

 描述（由适用提供）：干细胞具有出色的能力，可以发展成成人身体的一系列功能细胞类型，可用于修复受损或解剖的组织。尽管在实验室实现选择性分化方面取得了进步，但在移植后控制干细胞的命运仍然是未解决的挑战，也是使用干细胞作为治疗的重要障碍。发育过程中的干细胞规范由形态因子的一致作用（例如生长因子）策划，这些因子启动细胞内信号传导级联激活基因转录。干细胞表面的聚糖在确定生长因子与同源受体的相互作用方面起着关键作用。但是，它们的调节功能在差异化的选择性的背景下在很大程度上是出乎意料的。拟议项目的目的是创建用于操纵干细胞表面的聚糖结构的新技术，以调整体内细胞 - 矩阵界面上内源性生长因子的关联。提出了两种不同的方法来实现这一目标。第一种方法描述了在用纳米级糖基材料移植之前对干细胞表面的启动，具有对生长感兴趣的生长因子的亲和力。一旦将重塑的细胞输送到组织，这些材料将 促进内源生长因子的关联并激活信号传导和分化。第二种方法概述了这些材料的靶向递送到干细胞表面的体内与这些细胞中聚糖产生的抑制。这种原位重塑将使我们能够在关键连接处暂时覆盖天然聚糖信号，以实现生长因子信号传导和所需分化结果的选择性激活。这项工作将为再生医学领域的关键问题提供新的解决方案，并将为探索聚糖在干细胞技术，组织工程和生物医学中应用的丰富生物学开放新的机会。

项目成果

Glycocalyx Remodeling with Glycopolymer-Based Proteoglycan Mimetics.

使用基于糖聚合物的蛋白聚糖模拟物进行糖萼重塑。

• DOI: 10.1007/978-1-4939-3130-9_17
• 发表时间: 2016
• 期刊: Methods in molecular biology (Clifton, N.J.)
• 作者: Huang,MiaL;Smith,RaymondAA;Trieger,GregW;Godula,Kamil
• 通讯作者: Godula,Kamil

Biologically Derived Neoproteoglycans for Profiling Protein–Glycosaminoglycan Interactions

用于分析蛋白质与糖胺聚糖相互作用的生物衍生新蛋白聚糖

• DOI: 10.1021/acschembio.2c00205
• 发表时间: 2022
• 期刊: ACS Chemical Biology
• 影响因子: 4
• 作者: Porell, Ryan N.;Follmar, Julianna L.;Purcell, Sean C.;Timm, Bryce;Laubach, Logan K.;Kozirovskiy, David;Thacker, Bryan E.;Glass, Charles A.;Gordts, Philip L.;Godula, Kamil
• 通讯作者: Godula, Kamil

Glycocalyx Scaffolding to Control Cell Surface Glycan Displays.

• DOI: 10.1002/cpch.40
• 发表时间: 2018-06
• 期刊: Current protocols in chemical biology
• 作者: Huang ML;Tota EM;Verespy S 3rd;Godula K
• 通讯作者: Godula K

Stem Cell Microarrays for Assessing Growth Factor Signaling in Engineered Glycan Microenvironments.

• DOI: 10.1002/adhm.202101232
• 发表时间: 2022-03
• 期刊: Advanced healthcare materials
• 影响因子: 10
• 作者: Michalak AL;Trieger GW;Trieger KA;Godula K
• 通讯作者: Godula K

Following sugar patterns in search of galectin function.

遵循糖模式寻找半乳糖凝集素功能。

• DOI: 10.1073/pnas.1801039115
• 发表时间: 2018
• 期刊: Proceedings of the National Academy of Sciences of the United States of America
• 影响因子: 11.1
• 作者: Godula,Kamil