Synthetic substrates for the expansion and differentiation of hPSC-derived NPCs

用于 hPSC 衍生的 NPC 扩增和分化的合成底物

• 批准号: 9181880
• 负责人: DAVID A BRAFMAN
• 金额: $ 23.6万
• 依托单位: ARIZONA STATE UNIVERSITY-TEMPE CAMPUS
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-06-01 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9181880
• 关键词: Address; Alzheimer' s Disease; Amyotrophic Lateral Sclerosis; Animal Disease Models; Astrocytes; Biochemical Genetics; Bioreactors; Cell Line; Cell Proliferation; Cell Therapy; Cells; Chemicals; Chromosomal Stability; Development; Differentiation and Growth; Disease; Disease model; Electrophysiology (science); Engineering; Etiology; Extracellular Matrix; Glass; Goals; Growth; Health Care Costs; Heterogeneity; Human; Huntington Disease; In Vitro; Lead; Libraries; Life; Methods; Modeling; Morbidity - disease rate; Neuraxis; Neurodegenerative Disorders; Neuronal Differentiation; Neurons; Neurotransmitters; Oligodendroglia; Parkinson Disease; Pluripotent Stem Cells; Polymers; Population; Preclinical Drug Evaluation; Proliferating; Property; Public Health; Recombinants; Regenerative Medicine; Replacement Therapy; Research; Slide; Societies; Source; Spinal Muscular Atrophy; Stem cells; Supporting Cell; Suspension Culture; System; Technology; Therapeutic; United States; Variant; base; cell growth; cell type; chemical property; clinical application; design; effective therapy; functional group; high throughput technology; human disease; human embryonic stem cell; induced pluripotent stem cell; interest; mortality; multipotent cell; nerve stem cell; nervous system disorder; neuron loss; new therapeutic target; novel; physical property; relating to nervous system; scale up; symptom treatment; tool

PROJECT SUMMARY ABSTRACT Despite therapeutic advances, neurodegenerative diseases and disorders remain some of the leading causes of mortality and morbidity in the United States. Therefore, cell-based therapies to replace lost or damaged neurons or supporting neural cells are of great therapeutic interest. Human neural progenitor cells (hNPCs) derived from human pluripotent stem cells (hPSCs, including human embryonic stem cells [hESCs] and human induced pluripotent stem cells [hiPSCs]) can proliferate extensively and differentiate into all the neural lineages (i.e. neurons, astrocytes, and oligodendrocytes) that compromise the central nervous system (CNS). Therefore, hNPCs and their differentiated progeny could provide the cellular raw material to model or treat a variety of nervous system disorders. However, the clinical application of these cells will require (i) defined, xeno-free conditions for their expansion and neuronal differentiation and (ii) scalable culture systems that enable their expansion and neuronal differentiation in numbers sufficient for regenerative medicine and drug screening purposes. To that end, we will use a novel high-throughput approach to systematically screen a rationally designed library of physicochemically-defined polymers to identify candidate synthetic substrates for the expansion and neuronal differentiation of hNPCs. Next, we will use these synthetic substrates as the basis for the engineering of low shear bioreactor-based systems for large-scale hNPC expansion and neuronal differentiation. The scaled-up cell populations will be assessed for their heterogeneity as well as their cellular, biochemical, genetic, and electrophysiological properties. The successful completion of this research will significantly advance the clinical application of hNPCs and their derivatives as it will enable the large-scale expansion and neuronal differentiation of hNPCs in quantities necessary for disease modeling, drug screening, and regenerative medicine applications.

项目总结摘要 尽管治疗取得了进展，但神经退行性疾病和紊乱仍是一些主要原因。 美国的死亡率和发病率。因此，以细胞为基础的疗法来取代丢失或受损的 神经元或支持神经细胞具有极大的治疗价值。人神经前体细胞(HNPC) 来源于人类多能干细胞(HPSC)，包括人类胚胎干细胞[hESCs]和人类 诱导多能干细胞可广泛增殖并分化为多种神经细胞。 (即神经元、星形胶质细胞和少突胶质细胞)损害中枢神经系统(CNS)。 因此，hNPC及其分化的后代可以为建立或治疗APC提供细胞原料。 各种神经系统疾病。然而，这些细胞的临床应用将需要(I)明确， 其扩增和神经元分化的无Xeno条件以及(Ii)可扩展的培养系统 使其在足够数量的再生医学和药物中进行扩增和神经元分化 筛选目的。为此，我们将使用一种新的高通量方法来系统地筛选 合理设计的物理化学定义的聚合物文库，以确定候选合成底物 人神经前体细胞的扩增和神经元分化。接下来，我们将使用这些合成底物作为基础 用于基于低剪切生物反应器的大规模hNPC扩增和神经元系统的工程 差异化。放大的细胞群体将被评估它们的异质性以及它们的细胞， 生化、遗传和电生理特性。这项研究的成功完成将 极大地促进了人神经干细胞及其衍生物的临床应用，因为它将使大规模 扩增和神经元分化是疾病建模、药物筛选、 以及再生医学的应用。