A Microfluidic Bone Marrow Niche for the Study of Hematopoiesis

用于造血研究的微流控骨髓生态位

基本信息

批准号：
8572113
负责人：
Ying Zheng
金额：
$ 258.78万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-28 至 2018-06-30
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): The bone marrow produces nearly 500 billion blood cells per day in an adult human. Each type of blood cell is required for life: red blood cells deliver oxygen, white blood cells provide immunity, and platelets prevent bleeding, among other functions of these cells. Dysregulation of blood cell production leads to severe anemia, leukopenia, and thrombocytopenia, and produces substantial morbidity and mortality. Approximately 15 million red blood cell units, 9 million platelet units and thousands of stem cell units are transfused annually in the United States. Transfusion of donor-derived blood cells, however, raises many concerns, including the lack of control over quality and quantity, and the risk of infectious and bacterial contamination during storage and transfusion. New strategies to stimulate thrombopoiesis in vivo, or to produce sufficient numbers of blood cells in vitro would revolutionize the management of anemia and cytopenias. Important progress has been made towards tailoring the molecular biology and biochemical regulation of hematopoietic cells in culture. These approaches, however, are limited by their failure to reproduce the complexity of bone marrow architecture. Here we propose to develop an in vitro microfluidic bone marrow niche that recapitulates the bone marrow in its cellular and matrix components, but which can also be manipulated to determine the roles of each component in the functioning of a normal bone marrow, and allow us to elucidate and control hematopoiesis. Ideally, this system will be scalable, with the ultimate goal of generating blood cells in vitro for transfusion. Although much information has been learned about the mechanisms of hematopoiesis over the last several decades, a great deal remains unknown, particularly regarding the role of specific marrow niches in blood cell production. Recent advances in tissue engineering and vascular biology make it an opportune time to unravel these mysteries. The creation of the microfluidic bone marrow niche will represent the first in vitro system that recapitulates the complex architecture of the bone marrow, and functions to generate blood cells. Uniquely, this system allows the stepwise addition or removal of individual components of the niche to reveal their individual functions in blood cell production. The proposed work will not only be an important step towards understanding and controlling the hematopoietic development in both healthy and diseased states, but could also revolutionize preclinical testing for therapies to increase blood cell count in diseases where they are low, either because of the disease itself or its therapy. This system will also allow for optimization of the conditions for ex vivo production of blood cells. Once thes conditions are determined, the system can be scaled up to generate quantities sufficient for transfusion.

描述（由申请人提供）：骨髓每天在成年人中每天产生近5000亿个血细胞。每种类型的血细胞都需要生命：红细胞提供氧气，白细胞提供免疫力，而血小板则可以防止出血，以及这些细胞的其他功能。血细胞产生的失调会导致严重的贫血，白细胞减少和血小板减少症，并产生大量的发病率和死亡率。在美国，每年大约有1500万个红细胞单位，900万个血小板单位和数千个干细胞单元被输出。然而，供体衍生的血细胞的输血引起了许多担忧，包括缺乏对质量和数量的控制，以及在存储和输血期间传染和细菌污染的风险。在体内刺激血小板的新策略，或在体外产生足够数量的血细胞会彻底改变贫血和细胞质的治疗。在培养中造血细胞的分子生物学和生化调节方面取得了重要的进展。但是，这些方法受到未能再现骨髓结构复杂性的限制。在这里，我们建议开发一种体外微流体骨髓裂片，该骨髓概括其细胞和基质成分中的骨髓，但也可以操纵以确定每个成分在正常骨骨髓功能中的作用，并允许我们阐明和控制假子。理想情况下，该系统将是可扩展的，其最终目标是在体外产生血细胞以输血。尽管在过去的几十年中，已经了解了有关造血的机制的大量信息，但仍未清楚地了解，特别是关于特定骨髓壁ches在血细胞产生中的作用。组织工程和血管生物学的最新进展使得是揭开这些谜团的时机。微流体骨髓小裂的创建将代表第一个概括骨髓的复杂结构的体外系统，并起作用以产生血细胞。独特的是，该系统允许逐步添加或去除利基市场的各个组件，以揭示其在血细胞产生中的各个功能。拟议的工作不仅将是了解和控制健康状态和患病状态的造血发展的重要一步，而且还可以革新临床前测试疗法，以增加疾病本身或其疗法的疾病中血细胞计数的增加。该系统还将允许优化血细胞的体内产生条件。一旦确定了这些条件，就可以将系统缩放以产生足以输血的数量。