CAREER: Modeling Stem Cell Decision-Making During Vascularized Bone Development

1350554 Grayson，Warren L.为大型、不可愈合的骨缺损的治疗性再生提供血管化骨移植仍然是一个巨大的未得到满足的临床需求，每年在美国有100多万人受到影响。组织工程解决方案有可能极大地改进目前可用的治疗方法。这项研究的数据将被用来显著改进再生医学中设计功能性血管化骨移植的方法。这一职业项目的成果将被整合到PI教授的教育课程中，为学生提供进行尖端研究所需的工具，并提高对细胞和发育生物学的基本理解，因为它与组织工程有关。教育福利将扩大到国际学生，他们将通过密集的暑期实习接触到世界级的研究环境。该奖项还将通过建立变革性的实习计划，使处于危险中的少数族裔高中生受益。这项职业计划的总体目标是发展对干细胞在组织形成过程中致力于特定谱系的决定如何影响工程组织构造的结构和形态的基本理解。在细胞培养模型中，在血管化的骨形成过程中，间充质干细胞分化为周细胞(稳定新生血管形成)和成骨细胞(沉积矿物质)。成为周细胞或成骨细胞的决定因培养的空间和时间的不同而不同。这两种细胞类型对于适当组织结构的形成和维持都是至关重要的，但目前尚不清楚血管周围微环境如何影响干细胞向这两种特定表型之一的谱系规范。通过将组织工程细胞培养模型与分子生物学技术相结合，有可能探索调控复杂组织形成的复杂细胞命运决定。这一建议验证了一种假设，即作为空间(靠近血管结构)和时间的函数来调控间充质干细胞的周细胞/成骨细胞谱系承诺是形成完整的血管网络和矿化骨沉积的基础。主要的研究目标有三个：(1)确定细胞组成和生长因子对组织工程化血管化骨的结构和组织的影响。(Ii)评价生长因子浓度和空间梯度对组织结构的影响。(Iii)研究周细胞和成骨细胞的可塑性在调节血管化骨发育中的作用。这项职业奖由CBET部门的生物技术、生化和生物质工程项目共同资助，由材料研究部门的生物材料项目和数学科学部门的数学生物学项目共同资助。

1350554 Grayson, Warren L.The supply of vascularized bone grafts for the therapeutic regeneration of large, non-healing bone defects remains a huge unmet clinical need affecting more than one million people in the US every year. Tissue engineering solutions have the potential to significantly advance currently available treatment methods. The data from this study will be utilized to significantly improve approaches to engineer functional vascularized bone grafts for regenerative medicine. Results from this CAREER project will be integrated into the educational curricula taught by the PI, providing students with the tools needed to perform cutting-edge research and improve fundamental understanding of cell and developmental biology as it pertains to tissue engineering. The educational benefit will be extended to international students who will be exposed to world-class research environments through intensive summer internships. The award will also benefit 'at-risk' minority high school students through the establishment of a transformative internship program.The overall objective of this CAREER proposal is to develop a fundamental understanding of how the decision of stem cells to commit to a particular lineage during tissue formation impacts the structure and morphology of engineered tissue constructs. During vascularized bone formation in cell culture models, mesenchymal stem cells differentiate into pericytes (to stabilize the nascent vasculature) and osteoblasts (to deposit mineral). This decision to become pericyte or osteoblasts varies as a function of both space and time in culture. Both cell types are critical for the formation and maintenance of the appropriate tissue organization yet it remains unclear how the perivascular microenvironment impacts the lineage specification of stem cells into either of these particular phenotypes. By combining tissue engineering cell-culture models with molecular biology techniques it is possible to explore the intricate cell-fate decisions that regulate complex tissue formation. This proposal tests the hypothesis that regulating the pericyte/osteoblast lineage commitment of mesenchymal stem cells as a function of space (proximity to vascular structures) and time underlies the potential to form integrated vascular networks and mineralized bone deposits. There are three primary research objectives: (i) Determine the effect of cell composition and growth factor delivery on the structure and organization of tissue engineered vascularized bone. (ii) Evaluate effect of growth factor concentration and spatial gradients on tissue structure. (iii) Investigate the role of pericyte and osteoblast plasticity in mediating vascularized bone development.This CAREER award by the Biotechnology, Biochemical, and Biomass Engineering Program of the CBET Division is co-funded by the Biomaterials Program of the Division of Materials Research and by the Mathematical Biology Program of the Division of Mathematical Sciences.