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首页> 外文学位 >Generation and application of epithelial and epidermal cells derived from human pluripotent stem cells.
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Generation and application of epithelial and epidermal cells derived from human pluripotent stem cells.

机译：源自人多能干细胞的上皮和表皮细胞的产生和应用。

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摘要

Human pluripotent stem cells (hPSCs) offer a potential cell source for cell-based model systems to study development and disease, as well as for regenerative medicine due to their unique ability to self-renew or differentiate to any somatic cell type. Before the full potential of hPSCs can be realized, robust protocols must be developed to direct their fate. Researchers have identified various factors which can direct hPSC fate, such as those necessary for directing epithelial commitment of hPSCs. We have focused our efforts in refining methods for generating epithelial and epidermal cells from hPSCs and utilizing these somatic cells for various tissue engineering applications. We first developed a defined approach for generating epithelial and epidermal cells from hPSCs by identifying an optimal starting cell density to maximize yield and maintain high purity of simple epithelial progenitors. In addition, we demonstrated that the use of defined substrates, in lieu of undefined, xenogeneic substrates, can successfully facilitate efficient epithelial differentiation to produce functional keratinocyte progenitor cells that can terminally-differentiate to recapitulate epidermal tissue architecture in vitro. In a general application to be applied to any hPSC differentiation platform, we developed an approach to improve efficiency in and translate lab-scale hPSC differentiation systems to large-scale processes. Our integrated experimental and computational approach, using two epithelial differentiation systems as models, required the development of an ODE-based model and a fit of this model to data representing dynamics of various cell types present in culture. This fit was performed by estimating rate constants of cell fate decisions (self-renewal, differentiation, death). Sensitivity analyses on predicted rate constants indicated which cell fate decisions were limiting to the final cell yield. Finally, in a more specific application, we used our epithelial differentiation strategy for a more specific application in disease modeling. We derived patient-specific hiPSCs from patients with a genetic skin disorder and our preliminary findings indicate that the hiPSC-derived keratinocyte progenitors can recapitulate a diseased epidermal phenotype in vitro, providing a system to study this disease from a patient-specific cell source.
机译：人类多能干细胞（hPSC）为基于细胞的模型系统研究发育和疾病以及再生医学提供了潜在的细胞来源，因为它们具有自我更新或分化为任何体细胞类型的独特能力。在充分发挥hPSC的潜力之前，必须开发出可靠的协议来指导其命运。研究人员已经确定了可以指导hPSC命运的各种因素，例如指导hPSC上皮定向的必要因素。我们已集中精力改进从hPSC产生上皮和表皮细胞的方法，并将这些体细胞用于各种组织工程应用。我们首先通过确定最佳的起始细胞密度以最大化产量并维持简单上皮祖细胞的高纯度，开发了一种从hPSC生成上皮和表皮细胞的明确方法。此外，我们证明了使用定义的底物代替未定义的异种底物可以成功地促进有效的上皮分化，以产生功能性角化细胞祖细胞，该细胞可以最终分化为体外概括表皮组织结构。在可应用于任何hPSC分化平台的一般应用程序中，我们开发了一种方法来提高实验室规模的hPSC分化系统并将其转化为大规模流程的效率。我们的综合实验和计算方法，使用两个上皮分化系统作为模型，需要开发基于ODE的模型，并使该模型适合表示培养物中各种细胞类型动态的数据。通过估计细胞命运决定（自我更新，分化，死亡）的速率常数来进行拟合。对预测速率常数的敏感性分析表明哪些细胞命运决定限制了最终细胞产量。最后，在更具体的应用中，我们将上皮分化策略用于疾病建模中的更具体应用。我们从患有遗传性皮肤病的患者中获得了患者特异性的hiPSC，我们的初步发现表明，hiPSC衍生的角质形成细胞祖细胞可以在体外重现患病表皮的表型，从而提供了一种从患者特异性细胞来源研究该疾病的系统。

著录项

  • 作者

    Selekman, Joshua A.;

  • 作者单位

    The University of Wisconsin - Madison.;

  • 授予单位 The University of Wisconsin - Madison.;
  • 学科 Engineering Chemical.;Biology Cell.
  • 学位 Ph.D.
  • 年度 2013
  • 页码 148 p.
  • 总页数 148
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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