Tissue Engineering of Hematopoietic Bone

描述(申请人提供)：我们的长期目标是在体外工程造血骨，以治疗骨和造血疾病。这项应用的具体目标是生产包含骨髓的具有多潜能的、可再生的干细胞，以满足患者的长期再生需求，并为骨缺损的修复提供结构完整性。为了实现这一目标，我们组建了一支来自贝勒医学院(BCM)和莱斯的互动研究团队，他们在生物学和工程方面拥有必要的专业知识，其中包括：造血和干细胞生物学(Goodell，BCM)、骨发育(Davis，BCM)、血管发育(Hirschi，BCM和莱斯)、生物材料和生物反应器(West和Mikos，莱斯)以及生物成像(Barry和Sevick，BCM和莱斯)。我们的主要假设是，导致骨形成和功能骨髓和血管形成的步骤是可以在新生骨形成模型中分离和定义的；此外，通过了解这一过程所需的细胞和分子事件的序列和动力学，我们将深入了解如何在体外重现造血骨形成以促进多能造血干细胞的体外和体内增殖。为了解决这些假说，我们建立了一种新生骨形成模型，在该模型中，血管化的、充满骨髓的骨在体内生成，并证明在这种骨结构中形成的骨髓能够在体内存活和繁殖能够长期重建所有血细胞谱系的功能性HSC。我们已经开始解剖和定义导致造血骨形成的分子步骤，并建立了跟踪体内和体外骨髓来源细胞命运和功能所需的生物成像技术。我们设计并生产了能够使细胞存活和繁殖的生物材料，以及容易制造骨骼和血管的生物反应器。在这一应用中，我们将整合所有这些成分来工程造血骨，并在体外和体内测试其功能。此外，我们还与BCM和莱斯技术转移办公室建立了必要的联系，以促进我们的研究向生物技术和临床环境的过渡。

DESCRIPTION (provided by applicant): Our long-term goal is to engineer hematopoietic bone ex vivo to treat disorders of both bone and hematopoiesis. The specific goal of this application is to produce bone that contains marrow with pluripotent, repopulating stem cells that can fulfill the long-term regenerative needs of patients, as well as provide structural integrity for the repair of bone defects. To achieve this goal, we have assembled a team of interactive investigators from Baylor College of Medicine (BCM) and Rice that have the required expertise in biology and engineering, which includes: hematopoiesis and stem cell biology (Goodell, BCM), bone development (Davis, BCM), vascular development (Hirschi, BCM & Rice), biomaterials and bioreactors (West and Mikos, Rice) and bioimaging (Barry and Sevick, BCM and Rice). Our overarching hypotheses are that the steps that lead to bone formation and the establishment of functional marrow and vasculature are dissectible and definable in a model of de novo bone formation; furthermore, by understanding the sequence and kinetics of the cellular and molecular events needed for this process, we will gain insight into how to recapitulate hematopoietic bone formation ex vivo for the propagation of pluripotent HSC in vitro and in vivo. Toward addressing these hypotheses, we have established a model of de novo bone formation in which vascularized, marrow-filled bone was generated in vivo, and demonstrated that the marrow formed within this bone structure enables the survival and propagation of functional HSC that are capable of long-term reconstitution of all blood cell lineages in vivo. We have begun the dissect and define the molecular steps that lead to hematopoietic bone formation and have established bioimaging techniques needed to track the fate and function of marrow-derived cells ex vivo and in vivo. We have designed and generated biomaterials that will enable cellular survival and propagation, and bioreactors in which bone and blood vessels are readily fabricated. In this application, we will integrate all of these components to engineer hematopoietic bone and test its functions in vitro and in vivo. Furthermore, we have established necessary links to BCM and Rice technology transfer offices to facilitate the transition of our research into biotech and clinical settings.