Identifying the human skeletal stem cell.

识别人类骨骼干细胞。

• 批准号: 9975006
• 负责人: MICHAEL T LONGAKER
• 金额: $ 38.16万
• 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/9975006
• 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; 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; stem cells; 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.

项目摘要 该提议的项目的主要目标是识别和表征人类骨骼干细胞（HSSC） 以及其产生的骨骼，软骨和骨髓组织的谱系限制祖细胞。 基于我们最近在细胞详细介绍鼠标SSC的出版物的基础上，我们的最终目标是创建一个详细的 如在造血中所见，人类骨骼生成的谱图图具有多种脑细胞，产生了各种 在调节分化的利基市场中谱系。正如我们的鼠标研究所证明的那样，我们将通过 首先将人类骨骼干和祖细胞纯化至非常高的同质性（AIM 1），然后 其次，通过检查细胞子集的转录和翻译表达，最后 定义和探测茎和祖细胞之间的相互关系。因此，这些步骤将启用 我们制定如何操纵SSC利基市场以驱动骨头，软骨或骨髓的命运确定 基质以影响临床需求（AIM 2）。我们对MSSC利基法规的调查也使我们发现 骨形态发生蛋白-2，Wnt和VEGF的特定组合可能诱导从头形成 SSC甚至在非骨骼（脂肪）组织中。我们将探讨是否也可以诱导类似的形态组合 HSSC形成和从头产生的骨骼，软骨或基质来自丰富的人脂肪基质 种群（目标3）。 尽管小鼠模型有用，但最近的报告描述了小鼠和人之间的巨大差异 免疫学对新型治疗学的发展有直接影响。因此，为了真正 影响临床翻译，首先识别HSSC以识别保守的关键遗传途径是谨慎的 在小鼠和人类的骨骼生成中，并揭示了遗传机制 老鼠和人类。我们相信，实施MSSC策略后我们获得的专业知识 使我们处于一个独特的位置，以表征小鼠骨骼茎和祖细胞的人类对应物。 我们来自胎儿和成人组织的新的实质性初步人类骨骼茎/祖细胞数据 确认我们方法的技术可行性和HSSC的存在。提出的实验 如果得到支持，如果得到支持，将清除干细胞再生医学实际翻译的途径 骨骼疾病。