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Development of a microengineered approach for quantitative assessment of intercelluar communication in cell doublets and microscale tissue models.

机译：开发了一种微工程方法，用于定量评估细胞双峰和微观组织模型中的细胞间通讯。

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摘要

Intercellular communication plays important roles in maintaining structural and functional integrities of multicellular organisms. Among variant intercellular communication strategies, direct cell-to-cell communication via gap junction is performed by virtually all cell types in normal tissue. Understanding the mechanism of gap junction intercellular communication (GJIC) and its roles in various physiological and pathologic conditions is therefore the subject of extensive investigation. The predominant approaches for investigation of intercellular communications include examination of the expressions of gap junction proteins using molecular biological approaches, and assessment of gap junction permeability by measuring dye transfer, electrical conductance or metabolic cooperation. Although these approaches have proven successful in providing information of intercellular communication, they all suffer from some limitations that may restrict their applications in cardiac research, such as the inability to perform direct functional assessment, the insufficiency of spatial and temporal resolutions, or the incompatibility with high-throughput assays.;Newly developed microengineering technologies, on the other hand, largely excel traditional methods in spatial and temporal resolutions. These technologies are capable of creating electromechanical components at the length scales comparable to live cells. Their advances may shed lights on functional assessments of intercellular performance and therefore provide powerful platforms for studying intercellular communication. The aim of this study is to develop a microengineered approach to enable quantitative assessment of intercellular communication in cell doublets and microscale tissue models. Cell doublets isolated from cardiac muscle with well-preserved intercellular junctions are used as a physiologically relevant model. Selective electrical stimulation and electromechanical measurement are integrated in an in vitro platform so that the contractile performance due to electrical stimulation and that due to intercellular mechanical transduction can be separated, thus enabling quantitative assessment of intercellular performance by providing direct measures of cell contractility. The microengineered platform is applied for quantitative assessment of intercellular communications of adult cardiac myocytes in aortocaval fistula (ACF)-induced volume-overload heart failure model. The results reveal the therapeutic implications of this platform in optimizing treatment plans to improve contractile performance in various myocardium disorders. In addition, to perform quantitative assessment of intercellular communication in tissue constructs, microscale tissue models are developed by employing tissue engineering principles. The tissue scaffolds are fabricated by a novel method that combines the high-throughput manufacturing capability and the spatial patterning capability via technological combination of electrospray and microfabrication. The cells are then cultured on the tissue scaffolds to form microscale tissue models. Using the microengineered platform, the selective electrical stimulation is performed within these microscale tissue models for quantitatively assessing intercellular performance.;Collectively, this work provides a quantitative approach for studying intercellular communication in cell doublets and microscale tissue models, which is expected to advance the understanding of the role of intercellular communication in various physiologic or pathologic conditions, and hasten new tools for screening medications and drugs that target on regulation of intercellular junctions.
机译：细胞间通讯在维持多细胞生物的结构和功能完整性中起重要作用。在各种细胞间通讯策略中，几乎所有正常组织中的细胞类型都通过间隙连接进行直接的细胞间通讯。因此，了解间隙连接细胞间通讯（GJIC）的机制及其在各种生理和病理条件下的作用是广泛研究的主题。研究细胞间通讯的主要方法包括使用分子生物学方法检查间隙连接蛋白的表达，以及通过测量染料转移，电导或代谢合作来评估间隙连接通透性。尽管已证明这些方法可成功提供细胞间通讯信息，但它们都受到一些局限性的限制，这些局限性可能会限制其在心脏研究中的应用，例如无法执行直接功能评估，时空分辨率不足或与之不兼容。另一方面，新开发的微工程技术在空间和时间分辨率方面大大优于传统方法。这些技术能够以与活细胞相当的长度尺度制造机电组件。他们的进展可能为细胞间性能的功能评估提供了启发，因此为研究细胞间通讯提供了强大的平台。这项研究的目的是开发一种微工程方法，以定量评估细胞双峰和微观组织模型中的细胞间通讯。从具有良好保留的细胞间连接的心肌中分离出的细胞双峰被用作生理学相关模型。选择性电刺激和机电测量集成在体外平台中，因此可以将由于电刺激引起的收缩性能与由于细胞间机械转导引起的收缩性能分开，从而可以通过直接测量细胞收缩力来定量评估细胞间性能。该微工程平台用于定量评估主动脉瓣瘘（ACF）诱发的容量超负荷心力衰竭模型中成年心肌细胞的细胞间通讯。结果揭示了该平台在优化治疗计划以改善各种心肌疾病的收缩性能方面的治疗意义。另外，为了对组织构建体中的细胞间通讯进行定量评估，通过采用组织工程原理开发了微型组织模型。组织支架是通过新颖的方法制造的，该方法通过电喷雾和微细加工的技术结合将高通量的制造能力和空间构图能力相结合。然后将细胞培养在组织支架上以形成微型组织模型。使用微工程平台，在这些微型组织模型内进行选择性电刺激，以定量评估细胞间的性能。集体地，这项工作为研究细胞双峰和微型组织模型中的细胞间通讯提供了一种定量方法，有望促进人们的了解。揭示了细胞间通讯在各种生理或病理状况中的作用，并催生了用于筛选靶向细胞间连接调节的药物和药物的新工具。

著录项

  • 作者

    Zhang, Xu.;

  • 作者单位

    The Ohio State University.;

  • 授予单位 The Ohio State University.;
  • 学科 Biomedical engineering.
  • 学位 Ph.D.
  • 年度 2015
  • 页码 219 p.
  • 总页数 219
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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