BMP6 Induction of Human Mesenchymal Stem Cell Osteoblast Differentiation

BMP6 诱导人间充质干细胞成骨细胞分化

• 批准号: 7436259
• 负责人: Kurt David Hankenson
• 金额: $ 39.33万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-01 至 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7436259
• 关键词: Address; Adult; Affinity; Animal Model; Aspirate substance; Autologous; BMP2 gene; Back; Binding; Biocompatible Materials; Bioinformatics; Bone Morphogenetic Proteins; Bone Regeneration; Cell model; Cells; Cellular biology; Clinical Research; Collagen Type I; Collagraft; Condition; Defect; Development; Dexamethasone; Dose; Drug Delivery Systems; Endogenous Factors; Exhibits; Feedback; Gene Expression; Genes; Goals; Human; Implant; In Vitro; Kinetics; Lead; Learning; Marrow; Mediating; Mediator of activation protein; Mesenchymal; Mesenchymal Stem Cells; Modeling; Molecular; Mus; Natural regeneration; Numbers; Orthopedics; Osteoblasts; Osteogenesis; Pathway interactions; Patients; Pattern; Play; Principal Investigator; Process; Production; Protein Family; Proteins; RNA Interference; Range; Receptor Activation; Regulation; Relative (related person); Research Personnel; Rodent Model; Role; Role playing therapy; Scientist; Secondary to; Serum; Signal Pathway; Signal Transduction; Site; Skeletal Development; Stem cells; Stimulus; Surgeon; Testing; Therapeutic; Time; Tissue Engineering; Training; Transplantation; UC06; Up-Regulation; Work; autocrine; base; bone; cell type; computer studies; craniofacial; craniofacial repair; dosage; drug discovery; human embryonic stem cell; human embryonic stem cell line; implantation; in vivo; long bone; mathematical model; novel; pre-clinical; progenitor; programs; receptor; repaired; research study; response; subcutaneous; success; transcription factor

DESCRIPTION (provided by applicant): Our long-term programmatic goal is to utilize adult marrow-derived mesenchymal progenitors (mesenchymal stem cells - MSC) in tissue engineered constructs to repair craniofacial and long bone defects. MSC have robust potential to become osteoblasts and human MSC (hMSC) can form bone when implanted in heterotopic and orthotopic sites in animal models. A distinct advantage of exploiting the therapeutic potential of these stem cells is that autologous hMSC are easily cultivated from small marrow aspirates. Clinically, marrow could be collected from a patient, hMSC cultivated in vitro, and then delivered back to the patient. However, to most effectively use hMSC therapeutically, we must be able to fully control their differentiation. This requires a complete understanding of physiologically relevant factors that regulate hMSC differentiation, and in turn, downstream signaling and transcriptional networks that are activated. Our preliminary results show that bone morphogenetic-6 (BMP6) is an important autocrine mediator of hMSC differentiation. BMP6 is the only osteogenic BMP produced by hMSC and short-term treatment of cells with exogenous BMP6 promotes sustained expression of the osteogenic transcription factor osterix, leading to osteoblast differentiation. For this project we propose three specific aims: (1) we will examine the significance of endogenous BMP6 for osteoblast differentiation, (2) we will study BMP6 signaling that directs osteoblast differentiation, and (3) we will study the importance of BMP6-induced expression of osterix. These aims will be pursued in vitro, in vivo, and computationally by a team of investigators that includes a veterinary scientist and an orthopaedic surgeon - both trained as biochemists - and a computational biologist. Mechanistic experiments examining BMP6 function and cell signaling will be pursued in vitro and will utilize primary hMSC and human embryonic stem cells (lines WA01 and UC06). In vivo studies will use a preclinical heterotopic bone implantation model to examine the in vivo bone forming capacity of hMSC. Mathematical modeling will be used to describe kinetics of BMP6-induced osteoblast differentiation, and Bayesian learning will be used to discover signaling networks that are unique to BMP6-induced osteoblast differentiation. The completion of this five-year project will not only demonstrate the utility of BMP6 therapeutically to control hMSC osteoblast differentiation, but will also reveal novel signaling and transcriptional networks that govern hMC osteoblast differentiation. Long term, the identity of novel targets will lead to the development of enhanced therapeutic options for directing hMSC differentiation in tissue engineered constructs to repair bone.

描述（由申请人提供）：我们的长期规划目标是利用成体骨髓来源的间充质祖细胞（间充质干细胞- MSC）在组织工程构建体中修复颅面和长骨缺损。骨髓间充质干细胞（MSC）具有强大的成骨潜能，在动物模型中，人骨髓间充质干细胞（hMSC）在异位和正位植入后都能形成骨。利用这些干细胞的治疗潜力的一个明显优势是，自体造血干细胞很容易从小骨髓中培养出来。在临床上，可以从患者身上采集骨髓，在体外培养hMSC，然后再输送回患者体内。然而，为了最有效地利用造血干细胞进行治疗，我们必须能够完全控制它们的分化。这需要完全理解调节hMSC分化的生理相关因素，反过来，下游信号和转录网络被激活。我们的初步结果表明，骨形态发生-6 （bone morphogenesis -6, BMP6）是hMSC分化的重要自分泌介质。BMP6是hMSC产生的唯一成骨BMP，外源BMP6短期处理细胞可促进成骨转录因子osterix的持续表达，导致成骨细胞分化。对于这个项目，我们提出了三个具体目标：(1)我们将研究内源性BMP6对成骨细胞分化的意义，(2)我们将研究指导成骨细胞分化的BMP6信号传导，(3)我们将研究BMP6诱导成骨细胞表达的重要性。这些目标将在体外、体内和计算上由一组研究人员来实现，其中包括一名兽医科学家和一名整形外科医生——他们都是生物化学家——和一名计算生物学家。研究BMP6功能和细胞信号传导的机制实验将在体外进行，并将利用原代hMSC和人类胚胎干细胞（WA01和UC06系）。体内研究将使用临床前异位骨植入模型来检测hMSC的体内骨形成能力。数学模型将用于描述bmp6诱导成骨细胞分化的动力学，贝叶斯学习将用于发现bmp6诱导成骨细胞分化的独特信号网络。这项为期五年的项目的完成不仅将证明BMP6在治疗上控制hMC成骨细胞分化的实用性，而且还将揭示控制hMC成骨细胞分化的新信号和转录网络。从长远来看，新靶点的识别将导致在组织工程构建中指导hMSC分化以修复骨骼的增强治疗选择的发展。