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Generation of multilineage adrenal gland organoids using human pluripotent stem cells

使用人类多能干细胞生成多谱系肾上腺类器官

基本信息

批准号：
10286157
负责人：
Nadja Zeltner
金额：
$ 20.38万
依托单位：
UNIVERSITY OF GEORGIA
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-06 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10286157
关键词：
3-Dimensional Address Adrenal Cortex Adrenal Gland Diseases Adrenal Glands Adrenal Medulla Adrenal gland hypofunction Adult Affect Aldosterone Androgens Animals Architecture Biological Models Biology Blood Pressure Cell Communication Cell Lineage Cell Maturation Cell Therapy Cells Chromaffin Cells Color Complex Connective Tissue Data Development Disease Ectoderm Embryonic Development Endocrine Glands Epinephrine Evaluation Event Experimental Models Fatty acid glycerol esters Fluorescence Functional disorder Future Gene Expression Generations Genes Genetic Germ Layers Glucocorticoids Goals Growth Factor Hereditary Disease Homeostasis Hormones Human Human Development Immune system In Vitro Individual Intermediate Mesoderm Investigation Kidney Knowledge Life Literature Malignant Neoplasms Mesoderm Metabolic Metabolism Molecular Morphology Mus Nervous system structure Neural Crest Neural Crest Cell Norepinephrine Organ Organoids Process Regulation Regulator Genes Reporter Reporting Schwann Cells Stains Stress Structure System Tissues Toxic effect Toxin Transplantation Xenograft procedure Zona Fasciculata Zona Glomerulosa Zona Reticularis adult stem cell base capsule cell replacement therapy cell type human disease human pluripotent stem cell human tissue in vivo microphysiology system next generation progenitor response scale up single-cell RNA sequencing stem cell technology stem cells stressor tool

项目摘要

ABSTRACT/PROJECT SUMMARY The adrenal glands (AG) are critical endocrine organs that control the body’s response to stressors, metabolic challenges, blood pressure changes and immune system regulation. AG disease can be caused by many ailments, including genetic faults, malignancies and toxins, and both hyper- and hypofunction of the AGs can be lethal. The AG consists of a core called the medulla that is surrounded by a three-layered cortex, all wrapped in a capsule. It is known that the AGs develop from progenitors from two independent germ layers, i.e. ectoderm/neural crest cells giving rise to the AG medulla and mesoderm/intermediate mesoderm giving rise to the AG cortex. The AG undergoes dynamic cellular homeostasis throughout life driven by adult stem cells located in the capsule. Several open questions remain about the events leading to proper embryonic development of the human AGs, about their transformation and dysfunction in human disorders and about normal adult human homeostasis. Additionally, healthy human AG tissue might become crucial for transplantation approaches for the future treatment of AG disorders. The lack of a human experimental model system that can mimic the complexity of the human organ is causing a slow progression in answering such questions. 3D organoids, derived from human pluripotent stem cells (hPSCs) are ideal to address this gap, however no AG organoids have been reported to date. Here, we propose the generation of complex, assembled AG organoids from both neural crest and intermediate mesoderm progenitors. We will characterize the AG organoids in vitro and upon xenotransplantation based on molecular and functional entities. We will employ the AG organoids to ask questions about human embryonic development and assess their character on the single cell level. Our AG organoids will provide a platform to investigate future questions about AG biology and development, AG disease mechanisms, and ultimately provide the cellular material for cell therapy approaches for AG insufficiency.

摘要/项目总结肾上腺（AG）是控制身体对应激源、代谢和免疫反应的重要内分泌器官。挑战、血压变化和免疫系统调节。AG疾病可由多种原因引起疾病，包括遗传缺陷，恶性肿瘤和毒素，以及AG的功能亢进和功能减退，致命的AG由一个称为髓质的核心组成，髓质被三层皮质包围，所有皮质都包裹在一个胶囊已知AG是从来自两个独立胚层的祖细胞发育而来的，即，外胚层/神经嵴细胞产生AG髓质，中胚层/中间中胚层产生 AG皮质AG在整个生命过程中经历动态细胞稳态，由位于在太空舱里一些悬而未决的问题仍然存在的事件，导致适当的胚胎发育，人AG，它们在人类疾病中的转化和功能障碍，以及关于正常成年人体内平衡此外，健康的人AG组织可能成为移植方法的关键，未来的治疗AG障碍。缺乏一个人类实验模型系统，可以模仿的复杂性人体器官的解剖导致了回答这些问题的缓慢进展。3D类器官，来源于人类多能干细胞（hPSC）是解决这一差距的理想选择，然而，还没有AG类器官被据报道，到目前为止。在这里，我们建议从神经嵴和神经嵴中产生复杂的组装AG类器官。和中间中胚层祖细胞。我们将在体外表征AG类器官，基于分子和功能实体的异种移植。我们将使用AG类器官来询问关于人类胚胎发育的问题，并在单细胞水平上评估其特征。我们的AG 类器官将为研究未来关于AG生物学和发育、AG疾病机制，并最终为AG不足的细胞治疗方法提供细胞材料。