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首页> 外文学位 >Sculpting blood cells with actomyosin forces: The central role of myosin-II in biophysical regulation of megakaryopoiesis and early hematopoiesis.
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Sculpting blood cells with actomyosin forces: The central role of myosin-II in biophysical regulation of megakaryopoiesis and early hematopoiesis.

机译：用肌动球蛋白力雕刻血细胞：肌球蛋白II在巨核细胞生成和早期造血的生物物理调节中的核心作用。

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摘要

The human body generates 3 x 1010 nucleated blood cells, 2 x 1013 anucleated red blood cells and 1 x 1011 platelets (plts) every day. A number of soluble factors that control different aspects of hematopoiesis have been discovered, but the recapitulation of the ex vivo environment to program hematopoietic stem cells (HSCs) has been less successful. Bone marrow (BM) niches offer diverse mechanical cues to influence their resident cells, but their roles have been rarely investigated in the context of the hematopoietic system compared to large adherent cells, likely due to the impression that most blood cells are ‘non-adherent’ in culture and soft. However, most hematopoietic cells nevertheless express cytoskeletal and adhesion components. Given that cells sense mechanical cues predominantly via cellular contractility, this dissertation work investigates roles of non-muscle myosin-II (NMM-II), the major ATPase-dependent motor protein that converts biochemical to mechanical signals, in regulating two different ends of the adult hematopoiesis—megakaryocyte (MK) differentiation that leads to plt generation, and early HSC differentiation. Selective inhibitors against NMM-II, including blebbistatin, were used to first establish the importance of NMM-II in regulating both MK maturation with plt generation, and early HSC maintenance and differentiation. Then, a series of experiments were done to characterize the effects of NMM-II-mediated biophysical factors on hematopoiesis, including cytokinesis, cell membrane elasticity and matrix elasticity sensing. NMM-II can be regulated physiologically by the phosphorylation of the heavy chain. The site-specific signaling of the NMM-II phosphorylation is a common post-translational mechanism that can deactivate NMM-II in both mature MKs and early HSCs. The dissertation work introduces novel quantitative analyses of both global protein and mRNA expression profiles to define functional potentials of MKs in generating plts and engraftment potentials of HSCs in molecular terms. The functionality of MKs and HSCs modulated by NMM-II inhibition was tested by direct transplantation of human cells into xenograft mouse models for potential biomedical applications. In all, this work highlights NMM-II as a critical node for the biophysical regulation of adult hematopoiesis and identifies salient features of BM niches that can be used to enrich for functional MKs and HSCs.
机译：人体每天产生3 x 1010个有核血细胞，2 x 1013个无核红细胞和1 x 1011血小板（plts）。已经发现了许多控制造血功能不同方面的可溶性因子，但是对体外环境进行概括以对造血干细胞（HSC）进行编程却不太成功。骨髓（BM）壁ches可提供多种机械线索来影响其驻留细胞，但与大型贴壁细胞相比，在造血系统中很少研究它们的作用，这可能是由于大多数血细胞“不贴壁”的印象在文化和软。然而，大多数造血细胞仍表达细胞骨架和粘附成分。鉴于细胞主要通过细胞收缩力来感知机械信号，因此本论文研究了非肌肉肌球蛋白II（NMM-II）的作用，后者是主要的ATPase依赖性运动蛋白，可将生化信号转换为机械信号，从而调节细胞的两个不同末端。成人造血功能-导致形成plt的巨核细胞（MK）分化和早期HSC分化。首先，使用针对NMM-II的选择性抑制剂（包括抑菌素）来确立NMM-II在调节plt生成的MK成熟以及早期HSC维持和分化中的重要性。然后，进行了一系列实验以表征NMM-II介导的生物物理因素对造血的影响，包括细胞分裂，细胞膜弹性和基质弹性感测。 NMM-II可以通过重链的磷酸化进行生理调节。 NMM-II磷酸化的位点特异性信号传导是一种常见的翻译后机制，可以使成熟MK和早期HSC中的NMM-II失活。论文的工作介绍了新的定量分析的全球蛋白质和mRNA表达谱，以分子的方式定义MKs在产生斑点的功能潜力和HSCs的植入潜力。通过将人类细胞直接移植到异种移植小鼠模型中进行潜在的生物医学应用，测试了由NMM-II抑制调节的MK和HSC的功能。总之，这项工作突出了NMM-II作为成人造血功能的生物物理调节的关键节点，并确定了可用于丰富功能性MK和HSC的BM生态位的显着特征。

著录项

  • 作者

    Shin, Jae-Won.;

  • 作者单位

    University of Pennsylvania.;

  • 授予单位 University of Pennsylvania.;
  • 学科 Health Sciences Pharmacology.;Biophysics Biomechanics.;Engineering Biomedical.
  • 学位 Ph.D.
  • 年度 2011
  • 页码 194 p.
  • 总页数 194
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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