Biomimetic design of human induced pluripotent stem cells on a chip

芯片上人类诱导多能干细胞的仿生设计

• 批准号: 8621410
• 负责人: SHAOCHEN CHEN
• 金额: $ 19.38万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-30 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8621410
• 关键词: Acute; Address; Albumins; Alleles; Attention; Back; Biology; Biomimetics; Cell Survival; Cells; Clinical; Coculture Techniques; Complex; Confocal Microscopy; Cytochrome P450; Development; Disease; Drug Metabolic Detoxication; Encapsulated; Endothelial Cells; Ethics; Fibroblasts; Gene Expression Profile; Goals; Hepatic; Hepatic Tissue; Hepatocyte; Hepatology; Hepatotoxicity; Human; In Vitro; Liver; Mesenchymal Stem Cells; Metabolic; Modeling; Monitor; Morbidity - disease rate; Morphology; Nuclear; Optics; Patients; Pattern; Phase; Preclinical Drug Evaluation; Protocols documentation; Regenerative Medicine; Research; Rifampin; Source; Staining method; Stains; Structure; System; Talents; Techniques; Technology; Time; Tissue Engineering; Tissue Model; Tissues; Transplantation; Urea; Work; cell type; chronic liver disease; cost; design; drug metabolism; embryonic stem cell; enzyme activity; glucose-6-phosphatase; in vivo; induced pluripotent stem cell; liver function; metabolic abnormality assessment; mortality; multidrug resistance-associated protein 2; novel; pre-clinical; precursor cell; public health relevance; scaffold; stem cells; troglitazone

DESCRIPTION (provided by applicant): In the U.S., liver associated diseases are major contributors to morbidity and mortality. Approximately 40,000 people in the U.S. die each year from acute or chronic liver diseases. Liver tissue engineering has made significant progress towards the creation of in vitro liver models for drug screening, as well as in vivo constructs for addressing the large clinical need for transplant sources. However, cell sourcing remains a significant challenge for both in vivo and in vitro liver models. Human induced pluripotent stem cells (iPSCs) are a promising technology in regenerative medicine as they can be autologously derived, maintain high proliferative capacity, and demonstrate enormous differentiation potential, while also mitigating the ethical concerns associated with the use of embryonic stem cells (ESCs). However, the application of iPSCs towards functional in vitro tissue models is still largely under development, and tissue-engineered constructs for in vivo transplantation have yet to be fully realized. To address these challenging issues, we propose to develop a functional in vitro micro-liver model via encapsulation of pre-differentiated iPSCs using a novel 3D bioprinting technique. This model will be subsequently enhanced through the addition of physiologically related components (i.e. co-cultures with supportive cells) to provide an advanced liver-on-a-chip model that can be studied further. The liver associated functions of the liver-on-a-chip models will be systematically examined. In Specific Aim 1, we will develop a liver-on-a-chip model by encapsulating iPSC-derived hepatic progenitor cells within 3D biomimetic scaffolds. In Specific Aim 2, we propose to incorporate biologically related supportive cell types into the liver on-a-chip model. To accomplish our goal, we have assembled the collaborative talents of three experts, including Chen for biofabrication and tissue engineering, Wang for iPSCs, and Feng for hepatocellular function and liver biology. We envision that our patient specific liver-on-a chip model can be explored as a reliable and cost-efficient in vitro platform to facilitate drug metabolism studies, preclinical drug screening, and fundamental hepatology research.

描述（由申请人提供）：在美国，肝脏相关疾病是发病率和死亡率的主要原因。美国每年约有 40,000 人死于急性或慢性肝病。肝脏组织工程在创建用于药物筛选的体外肝脏模型以及用于药物筛选的体内构建方面取得了重大进展。 满足临床对移植来源的巨大需求。然而，细胞来源对于体内和体外肝脏模型仍然是一个重大挑战。人类诱导多能干细胞（iPSC）是再生医学中一项有前途的技术，因为它们可以自体衍生，保持高增殖能力，并表现出巨大的分化潜力，同时还减轻与使用胚胎干细胞（ESC）相关的伦理问题。然而，iPSC 在功能性体外组织模型中的应用仍在很大程度上处于开发阶段，用于体内移植的组织工程构建体尚未完全实现。为了解决这些具有挑战性的问题，我们建议通过使用新型 3D 生物打印技术封装预分化 iPSC 来开发功能性体外微肝脏模型。随后将通过添加生理相关成分（即与支持细胞共培养）来增强该模型，以提供可以进一步研究的先进肝脏芯片模型。将系统地检查肝脏芯片模型的肝脏相关功能。在具体目标 1 中，我们将通过将 iPSC 衍生的肝祖细胞封装在 3D 仿生支架内来开发肝脏芯片模型。在具体目标 2 中，我们建议将生物学相关的支持细胞类型纳入肝脏 片上模型。为了实现我们的目标，我们聚集了三位专家的协作人才，其中包括生物制造和组织工程领域的 Chen、iPSC 领域的 Wang 以及肝细胞功能和肝脏生物学领域的 Feng。我们设想，我们的患者特异性肝脏芯片模型可以作为可靠且具有成本效益的体外平台进行探索，以促进药物代谢研究、临床前药物筛选和基础肝病学研究。