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（由申请人提供）：干细胞具有发育成可用于修复受损或患病组织的一系列成人身体功能细胞类型的显著能力。尽管在实验室中实现选择性分化方面取得了进展，但控制移植后干细胞的命运仍然是一个未解决的挑战，也是使用干细胞作为治疗剂的重大障碍。发育过程中的干细胞特化是由形态发生素（如生长因子）的协同作用协调的，这些形态发生素启动细胞内信号级联激活基因转录。干细胞表面的聚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尚未被探索。拟议项目的目的是创造新的技术，用于操纵干细胞表面的聚糖结构，以调节体内细胞-基质界面处内源性生长因子的缔合。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移植之前用对感兴趣的生长因子具有亲和力的纳米级糖模拟物材料引发干细胞表面。一旦重塑的细胞被递送到组织中，这些材料将 促进内源性生长因子的结合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体内干细胞的表面，伴随着这些细胞中聚糖产生的抑制。这种原位重塑将使我们能够暂时覆盖关键连接处的天然聚糖信号，以实现生长因子信号传导的选择性激活和期望的分化结果。这项工作将为再生医学领域的一个关键问题提供一种新的解决方案，并将为探索用于干细胞技术、组织工程和生物医学的聚糖的丰富生物学提供新的机会。

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

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

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