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）： 各种细胞类型的分层且严格控制的组织是正常组织和器官的标志，该提议的假设是，预先定义 3D 组织结构内单个细胞的具体位置和由此产生的细胞-细胞相互作用将允许创建高功能组织，其中细胞间相互作用对细胞表型的作用可以被精确描述。我们将通过开发人类造血的 3D 模型来探索这一概念，其中将探讨骨祖细胞和血管细胞在定义造血干细胞 (HSC) 生态位中的作用。具体目标包括（1）开发微流体技术，允许将单细胞大规模封装在高度定义的细胞外基质模拟物中，以确定基质线索如何在单细胞水平上调节间充质干细胞分化，（2）创建混合集成电路/微流体电路系统，使人们能够将含有单个细胞和合成 ECM 的皮升液滴组装成具有预定义结构和组织的 3D 组件，以及 (3) 确定 HSC 是否适合体外组装代表骨髓HSC生态位的细胞可以产生能够在体外重建造血功能的功能性造血组织。该项目的成功将导致创建一套新的工具，这些工具将能够形成具有精确定义的细胞放置以及同型和异型细胞间相互作用的 3D 组织。这些工具可能广泛用于创建组织发育和药物筛选的新体外模型，以及各种细胞类型的体内组织替代品。由于干细胞对环境因素特别敏感，不适当的细胞-细胞和细胞-基质相互作用可能会导致培养物中发现的干细胞分化命运发生不可逆和不良的改变。该项目开发的系统将使我们能够研究血管细胞和骨祖细胞/成骨细胞在维持人类 HSC 生态位中的具体作用，这是一个在体内很难解决的问题。更好地定义和创建生态位模型对于了解正常造血和涉及血细胞的病理学以及在各种治疗场所实现按需造血至关重要。迄今为止，关于这一主题的关键研究都依赖于啮齿动物模型，许多研究结果与人类生物学的相关性目前尚不清楚。 （审稿人评论结束）

项目成果

Macroscale delivery systems for molecular and cellular payloads.

用于分子和细胞有效负载的宏观递送系统。

• 发表时间: 2013-11
• 影响因子: 41.2
• 作者: Kearney, Cathal J;Mooney, David J
• 通讯作者: Mooney, David J

Regenerative medicine: Current therapies and future directions.

再生医学：当前的疗法和未来的方向。

• 发表时间: 2015-11-24
• 影响因子: 11.1
• 作者: Mao, Angelo S;Mooney, David J
• 通讯作者: Mooney, David J

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

用于长期 3D 培养的单细胞负载蛋白酶敏感微生态位。

• 发表时间: 2017-02-14
• 影响因子: 6.1
• 作者: Lienemann, Philipp S;Rossow, Torsten;Mao, Angelo S;Vallmajo;Ehrbar, Martin;Mooney, David J
• 通讯作者: Mooney, David J

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。

• 发表时间: 2016-04-21
• 影响因子: 6.1
• 作者: Chen, Qiushui;Utech, Stefanie;Chen, Dong;Prodanovic, Radivoje;Lin, Jin;Weitz, David A
• 通讯作者: Weitz, David A

Tumor-Vasculature-on-a-Chip for Investigating Nanoparticle Extravasation and Tumor Accumulation.

用于研究纳米颗粒外渗和肿瘤积累的肿瘤血管芯片。

• 发表时间: 2018
• 影响因子: 17.1
• 作者: Wang, Hao;Ran, Rui;Liu, Yun;Hui, Yue;Zeng, Bijun;Chen, Dong;Weitz, David A;Zhao, Chun
• 通讯作者: Zhao, Chun