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Physicochemical control of multilineage emergence

多谱系出现的物理化学控制

基本信息

批准号：
10714338
负责人：
Quinton Smith
金额：
$ 37万
依托单位：
UNIVERSITY OF CALIFORNIA-IRVINE
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-08-01 至 2028-07-31
项目状态：
未结题

项目摘要

Project Summary Human induced pluripotent stem cells (iPSCs) are unique in that they retain their ability to indefinitely self-renew while maintaining the capacity to self-organize and differentiate into both embryonic and extraembryonic lineages. iPSCs have emerged as a powerful tool to study human development, and disease, and have been integrated with tissue engineering approaches for regenerative medicine applications. To fulfill the promise of iPSC clinical utility, further investigation of the role of the stem cell niche in iPSC morphogenesis, lineage specification, and functional maturation is needed. While organoid approaches have revolutionized our ability to mimic organ-level function in a dish, they typically are comprised of cells from a single germ layer, missing critical cues shared by surrounding populations including the microvasculature and stroma. In addition, organoids are generated in ill-defined matrices such as Matrigel, which suffers from batch-to-batch variation, and limited tunability. To this end, we propose using micropatterned induced gastrulation models to better understand how paracrine and mechanical cues guide primitive stem cell fate. In addition, by leveraging assembloid technologies, synthetic extracellular matrix mimics, and dynamic microfluidic culture, we aim to better understand multi-germ layer interactions during tissue specification. Finally, we propose that improved iPSC derivatives can be used to better understand patient-specific differences in metabolic disorders. Collectively, we propose that using an integrative approach will permit iPSCs to be a powerful testbed for studying developmental biology and disease processes.

项目摘要人类诱导多能干细胞（iPSC）的独特之处在于它们保留了无限期自我更新的能力，同时保持自我组织和分化成胚胎和胚外的能力血统iPSC已经成为研究人类发育和疾病的有力工具，与再生医学应用的组织工程方法相结合。履行…的诺言 iPSC临床效用，进一步研究干细胞生态位在iPSC形态发生、谱系规范和功能成熟是必要的。虽然类器官方法已经彻底改变了我们的能力，在培养皿中模拟器官水平的功能，它们通常由来自单个胚层的细胞组成，包括微血管和基质在内的周围人群共享的线索。此外，类器官是在定义不清的基质（如Matrigel）中生成，其存在批次间差异，可调性为此，我们建议使用微模式诱导原肠胚形成模型来更好地了解如何旁分泌和机械信号引导原始干细胞的命运。此外，通过利用仿人技术，合成细胞外基质模拟物和动态微流控培养，我们的目标是更好地了解多细菌组织规范期间的层相互作用。最后，我们建议可以使用改进的iPSC衍生物以更好地了解代谢紊乱的患者特异性差异。总的来说，我们建议使用综合方法将使iPSC成为研究发育生物学和疾病的强大试验平台流程.