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/项目摘要肾上腺（Ag）是控制人体对压力源的反应，代谢的关键内分泌器官挑战，血压变化和免疫系统调节。 AG疾病可能是由许多人引起的疾病，包括遗传断层，疟疾人和毒素，以及AG的超功能和功能障碍致命。 AG由一个名为髓质的核心组成，被三层皮质包围，全部包裹在胶囊。众所周知，AG是从两个独立细菌层的祖细胞中发展出来的，即外胚层/神经rest细胞产生Ag髓质和中胚层/中胚层产生 Ag皮质。 AG在成年干细胞驱动的整个生命中都经历了动态细胞稳态在胶囊中。关于事件导致适当的胚胎发展的事件仍然存在一些开放性问题人类AGS关于人类疾病的转变和功能障碍以及正常的成年人稳态。此外，健康的人类AG组织可能对移植方法至关重要未来对AG疾病的治疗。缺乏可以模仿复杂性的人类实验模型系统人体器官的回答在回答此类问题时会导致缓慢的进展。 3D器官，源自人类多能干细胞（HPSC）是解决此差距的理想选择，但是没有AG器官迄今已报告。在这里，我们提出了两个神经rest的复合物组装的Ag类器官和中间中胚层祖细胞。我们将在体外和在基于分子和功能实体的异种移植。我们将采用AG器官问关于人类胚胎发育和评估其特征在单细胞水平上的问题。我们的农业类器官将提供一个平台，调查有关AG生物学和发展，AG病的未来问题机制，并最终为AG不足提供细胞疗法方法提供了细胞材料。