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The Effect of Cytoskeletal Perturbation on Pluripotent Stem Cell Differentiation

机译：细胞骨架微扰对多能干细胞分化的影响

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摘要

Pluripotent stem cells (PSCs) have the ability to self-renew and differentiate to all cell types in the body, making them an attractive source for cell-based tissue engineering and regenerative medicine applications. The use of these cells, however, relies on a thorough understanding of the mechanisms that regulate PSC fate including the maintenance of pluripotency and differentiation. Most protocols designed to direct differentiation rely on the control of biochemical cues. This dissertation instead focuses on the potential to modulate the cytoskeleton, a network of interconnected structural proteins known to modulate adult stem cell fate, to regulate PSC differentiation.;Here we found that cytoskeletal expression, including actin and intermediate filaments, in PSCs is unique compared to adult phenotypes and these cells undergo cytoskeletal remodeling with differentiation. The intermediate filament vimentin plays a critical role during PSC differentiation as the lack of vimentin in knockout PSCs altered differentiation to mesodermal and endothelial phenotypes. Perturbation of vimentin further modulated the organization and development of other cytoskeletal structures indicating the importance of the interconnected nature of the cytoskeleton and identifying other proteins that could potentially regulate PSC differentiation. Lastly, actin polymerization and actin-myosin interactions were also identified as targets that could be modulated through the use of small molecules to direct differentiation of PSCs.;Taken together, these studies highlight the importance of the cytoskeleton as a regulator of PSC differentiation. Modulation of the cytoskeleton, not only biochemical cues, could be used to control differentiation pathways in PSCs. The work presented here can be used to improve the design of directed differentiation protocols needed for the use of PSCs in tissue engineering and regenerative medicine-based applications.
机译：多能干细胞（PSC）具有自我更新和分化为体内所有细胞类型的能力，使其成为基于细胞的组织工程和再生医学应用的有吸引力的来源。然而，这些细胞的使用依赖于对调节PSC命运的机制的透彻了解，包括维持多能性和分化。旨在指导分化的大多数方案都依赖于生化线索的控制。相反，本文着重于调节细胞骨架的潜力，该细胞骨架是相互连接的结构蛋白网络，可调节成年干细胞的命运，以调节PSC的分化;在此我们发现，相比于PSC，细胞骨架的表达（包括肌动蛋白和中间丝）具有独特性到成年表型，这些细胞经历分化的细胞骨架重塑。中间丝波形蛋白在PSC分化过程中起关键作用，因为敲除PSC中波形蛋白的缺乏改变了对中胚层和内皮表型的分化。波形蛋白的微扰进一步调节了其他细胞骨架结构的组织和发展，表明了细胞骨架相互联系的性质的重要性，并确定了可能调节PSC分化的其他蛋白质。最后，肌动蛋白聚合和肌动蛋白-肌球蛋白的相互作用也被确定为可通过使用小分子指导PSC分化的靶标。综上所述，这些研究突显了细胞骨架作为PSC分化调节剂的重要性。细胞骨架的调节，不仅是生化线索，还可以用于控制PSCs的分化途径。本文介绍的工作可用于改进组织工程和再生医学应用中使用PSC所需的定向分化方案的设计。

著录项

  • 作者

    Boraas, Liana C.;

  • 作者单位

    Tulane University School of Science and Engineering.;

  • 授予单位 Tulane University School of Science and Engineering.;
  • 学科 Bioengineering.
  • 学位 Ph.D.
  • 年度 2017
  • 页码 235 p.
  • 总页数 235
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 物理化学（理论化学）、化学物理学;
  • 关键词

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