Identifying the human skeletal stem cell.

识别人类骨骼干细胞。

• 批准号: 9756366
• 负责人: MICHAEL T LONGAKER
• 金额: $ 38.11万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-06 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9756366
• 关键词: Address; Adipose tissue; Adult; Affect; Aging; BMP2 gene; Bone Marrow; Cartilage; Cell Lineage; Cells; Chondrogenesis; Clinical; Data; Development; Disease; Family; Foundations; Generations; Genetic; Genetic Transcription; Goals; Hematopoiesis; Hematopoietic System; Human; Human Activities; Immunology; In Situ; In Vitro; Individual; Investigation; Maintenance; Malignant Neoplasms; Maps; Mesenchymal; Mesenchyme; Multipotent Stem Cells; Mus; Muscle; Natural regeneration; Osteogenesis; Pathway interactions; Physiologic Ossification; Play; Population; Positioning Attribute; Publications; Published Comment; Recipe; Regenerative Medicine; Regulation; Reporting; Role; Scheme; Signal Transduction; Skeletal system; Skeleton; Stem cells; Stromal Cells; Testing; Tissues; Translations; Trauma; United States; Vascular Endothelial Growth Factors; Work; bone; bone morphogenetic protein 2; clinical translation; experimental study; fetal; human fetal cells; in vivo; morphogens; mouse model; novel therapeutics; progenitor; programs; prospective; regenerative; self-renewal; skeletal; skeletal disorder; skeletal tissue; skeletogenesis; stem; stem cell niche; stromal progenitor

Project Summary The primary goal of this proposed project is to identify and characterize the human skeletal stem cell (hSSC) and the lineage restricted progenitors of bone, cartilage, and bone marrow stromal tissues that it generates. Building on our recent publication in Cell detailing the mouse SSC, our ultimate objective is to create a detailed lineage map of human skeletogenesis, as seen in hematopoiesis, with a mulitpotent stem cell generating various lineages in a niche that regulates differentiation. As demonstrated in our mouse study, we will achieve this by first purifying human skeletal stem and progenitor cells to a very high level of homogeneity (Aim 1) and then secondly by examining the transcriptional and translational expression of the cellular subsets, before finally defining and probing the inter-relationship between the stem and progenitor cells. These steps will, thus, enable us to strategize how to manipulate the SSC niche to drive fate determination of bone, cartilage or bone marrow stroma to affect clinical need (Aim 2). Our investigation of the mSSC niche regulation also led us to discover specific combinations of bone morphogenetic protein-2, Wnt and VEGF that could induce de novo formation of SSC even in non-skeletal (adipose) tissue. We will explore if similar morphogen combinations could also induce hSSC formation and de novo generation of bone, cartilage, or stroma from plentiful human adipose stromal populations (Aim 3). Despite the utility of mouse models, recent reports describe dramatic differences between mouse and human immunology, which has a direct impact on the development of novel therapeutics. Therefore, in order to truly affect clinical translation, it is prudent to first identify the hSSC to identify key genetic pathways that are conserved in mouse and human skeletogenesis and to reveal the genetic mechanisms underlying differences between mouse and humans. We are confident that the expertise we acquired upon implementation of our mSSC strategy puts us in a unique position to characterize human counterparts of the mouse skeletal stem and progenitor cell. Our new substantial preliminary human skeletal stem/progenitor data from both fetal and adult tissue strongly affirm the technical feasibility of our approach and the existence of the hSSC. The proposed experiments in this application, if supported, would clear the path to practical translation of stem cell regenerative medicine for skeletal diseases.

项目概要 该项目的主要目标是识别和表征人类骨骼干细胞（hSSC） 谱系限制了它产生的骨、软骨和骨髓基质组织的祖细胞。 基于我们最近在 Cell 上发表的详细介绍小鼠 SSC 的文章，我们的最终目标是创建一个详细的 人类骨骼发生的谱系图，如造血过程中所见，多能干细胞产生各种 调节分化的利基中的谱系。正如我们的小鼠研究所证明的，我们将通过以下方式实现这一目标 首先将人类骨骼干细胞和祖细胞纯化至非常高的同质性水平（目标 1），然后 其次通过检查细胞亚群的转录和翻译表达，最后 定义和探讨干细胞和祖细胞之间的相互关系。因此，这些步骤将使 我们制定策略，如何操纵 SSC 生态位来驱动骨骼、软骨或骨髓的命运决定 基质影响临床需求（目标 2）。我们对 mSSC 利基监管的调查还发现 骨形态发生蛋白-2、Wnt 和 VEGF 的特定组合可诱导骨形态发生蛋白从头形成 SSC 甚至存在于非骨骼（脂肪）组织中。我们将探索类似的形态发生素组合是否也可以诱导 hSSC 的形成以及从大量人类脂肪基质中从头生成骨、软骨或基质 人口（目标 3）。 尽管小鼠模型很实用，但最近的报告描述了小鼠和人类之间的巨大差异 免疫学，对新疗法的开发有直接影响。因此，为了真正 影响临床转化，谨慎的做法是首先鉴定 hSSC，以确定保守的关键遗传途径 小鼠和人类骨骼发生过程中的研究，并揭示之间差异背后的遗传机制 老鼠和人类。我们相信，我们在实施 mSSC 战略时获得的专业知识 使我们处于独特的地位来表征小鼠骨骼干细胞和祖细胞的人类对应物。 我们来自胎儿和成人组织的新的大量初步人类骨骼干/祖细胞数据强烈 确认我们的方法的技术可行性以及 hSSC 的存在。本中提出的实验 如果获得支持，该应用将为干细胞再生医学的实际转化扫清道路 骨骼疾病。