Building the Hematopoietic Stem Cell Niche

建立造血干细胞生态位

• 批准号: 8704933
• 负责人: David J Mooney
• 金额: $ 77.99万
• 依托单位: HARVARD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-15 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8704933
• 关键词: 3-Dimensional; Address; Animal Model; Blood; Blood Cells; Blood Vessels; Bone Marrow; Cell Communication; Cell Culture System; Cells; Complement; Cues; Development; Disease; Drops; Extracellular Matrix; Hematopoiesis; Hematopoietic stem cells; Human; Human Biology; Hybrids; In Vitro; Individual; Lead; Location; Mesenchymal Stem Cells; Microfluidics; Modeling; Normal tissue morphology; Organ; Osteoblasts; Pathology; Patients; Phenotype; Play; Preclinical Drug Evaluation; Process; Production; Published Comment; Rodent Model; Role; Stem cells; Structure; System; Techniques; Technology; Therapeutic; Time; Tissues; base; cell assembly; cell associated matrix; cell type; design; hematopoietic tissue; improved; in vitro Model; in vivo; insight; osteoprogenitor cell; reconstitution; stem cell differentiation; stem cell niche; success; three-dimensional modeling; tool

DESCRIPTION (provided by applicant): A hierarchal and tightly controlled organization of various cell types is the hallmark of normal tissues and organs, and the hypothesis underlying this proposal is that pre-defining the specific location and resultant cell- cell interactions of individual cells within a 3D tissue construct will allow one to create highly functional tissues in which the role of cell-cell interactions on cell phenotype can be precisely delineated. This concept will be explored by developing a 3D model of human hematopoiesis, in which osteoprogenitors and vascular cells will be probed for their roles in defining the hematopoietic stem cell (HSC) niche. The specific aims include (1) the development of microfluidic techniques to allow large-scale encapsulation of single cells in highly defined extracellular matrix mimics in order to determine how matrix cues regulate mesenchymal stem cell differentiation at the single cell level, (2) the creation of hybrid integrated circuit/microfluidic circuit systems to enable one to assemble picoliter drops containing individual cells and synthetic ECM into 3D assemblies with pre-defined structure and organization, and (3) determining whether appropriate in vitro assembly of HSCs and cells representative of the bone marrow HSC niche can yield functional hematopoietic tissues capable of recreating hematopoiesis in vitro. Success in this project will lead to the creation of a new set of tools that will enable formation of 3D tissues with precisely defined cell placement, and homotypic and heterotypic cell-cell interactions. These tools are likely to be broadly useful to the creation of new in vitro models of tissue development and drug screening, and in vivo tissue replacements from a variety of cell types. As stem cells are particularly sensitive to environmental cues, inappropriate cell-cell and cell-matrix interactions likely lead to the irreversible and undesirable alterations in stem cell differentiation fate found in culture. The systems developed in this project will allow us to investigate the specific role of vascular cells and osteoprogenitors/osteoblasts in maintaining the human HSC niche, which is a difficult question to address in vivo. It is crucial to better define and create models of the niche to understand normal hematopoiesis and pathologies involving blood cells, and to enable hematopoiesis on demand in various therapeutic venues. The key studies to date on this topic have relied on rodent models, and the relevance of many findings to human biology is currently unclear. (End of Reviewers' Comment)

描述（由申请人提供）： 正常组织和器官的标志是，该提案的基本假设是预先定义特定位置以及3D组织中单个细胞在3D组织中的单个细胞的相互作用将允许一个人可以创建高度功能性的组织，而细胞细胞在细胞现象上的作用可以精确地替代细胞的作用。将通过开发人类造血的3D模型来探索这个概念，其中将骨化剂和血管细胞用于定义造血干细胞（HSC）小裂市场中的作用。具体目的包括（1）微流体技术的发展，以使单个细胞在高度定义的细胞外基质中大规模封装模拟模拟物，以确定矩阵提示如何调节间充质干细胞分化在单个细胞水平上的间质干细胞分化，（2）将杂种电路系统置于综合系统中，以使单个细胞构成一个启用ecomem insemper insemper consemption consemption insemple insemple insemple insemple insemple insemple sandement insemple symement insemple sander consemption consemption consempt具有预定义的结构和组织的3D组件，以及（3）确定代表骨髓HSC元素的HSC和细胞的适当体外组装是否可以产生能够在体外重现造血的功能性造血组织。该项目的成功将导致创建一组新的工具，这些工具将使能够形成具有精确定义的细胞放置以及同型和异型细胞细胞相互作用的3D组织。这些工具可能对创建新的组织发育和药物筛选的新体外模型以及体内组织替代各种细胞类型的替代物可能广泛有用。由于干细胞对环境线索特别敏感，因此不适当的细胞 - 细胞和细胞 - 基质相互作用可能导致在培养中发现的干细胞分化命运的不可逆和不良改变。该项目中开发的系统将使我们能够研究血管细胞和骨基因生成剂/成骨细胞在维持人类HSC利基市场中的特定作用，这是在体内很难解决的问题。更好地定义和创建利基模型以了解涉及血细胞的正常造血和病理学，并在各种治疗场所的需求下造血至关重要。迄今为止，有关该主题的关键研究依赖于啮齿动物模型，目前尚不清楚许多发现与人类生物学的相关性。 （审稿人的评论结束）

项目成果

Single cell-laden protease-sensitive microniches for long-term culture in 3D.

• DOI: 10.1039/c6lc01444e
• 发表时间: 2017-02-14
• 期刊: Lab on a chip
• 影响因子: 6.1
• 作者: Lienemann PS;Rossow T;Mao AS;Vallmajo-Martin Q;Ehrbar M;Mooney DJ
• 通讯作者: Mooney DJ

3D Printed Microtransporters: Compound Micromachines for Spatiotemporally Controlled Delivery of Therapeutic Agents.

• DOI: 10.1002/adma.201503095
• 发表时间: 2015-11
• 期刊: Advanced materials (Deerfield Beach, Fla.)
• 作者: Huang TY;Sakar MS;Mao A;Petruska AJ;Qiu F;Chen XB;Kennedy S;Mooney D;Nelson BJ
• 通讯作者: Nelson BJ

Controlled assembly of heterotypic cells in a core-shell scaffold: organ in a droplet.

核壳支架中异型细胞的受控组装：液滴中的器官

• DOI: 10.1039/c6lc00231e
• 发表时间: 2016-04-21
• 期刊: Lab on a chip
• 影响因子: 6.1
• 作者: Chen Q;Utech S;Chen D;Prodanovic R;Lin JM;Weitz DA
• 通讯作者: Weitz DA

Controlled self-assembly of alginate microgels by rapidly binding molecule pairs.

• DOI: 10.1039/c7lc00500h
• 发表时间: 2017-07-11
• 期刊: Lab on a chip
• 影响因子: 6.1
• 作者: Hu Y;Mao AS;Desai RM;Wang H;Weitz DA;Mooney DJ
• 通讯作者: Mooney DJ

High-throughput double emulsion-based microfluidic production of hydrogel microspheres with tunable chemical functionalities toward biomolecular conjugation

• DOI: 10.1039/c7lc01088e
• 发表时间: 2018-01-21
• 期刊: LAB ON A CHIP
• 影响因子: 6.1
• 作者: Liu, Eric Y.;Jung, Sukwon;Choi, Chang-Hyung
• 通讯作者: Choi, Chang-Hyung