Osteoblastic Activation in the Hematopoietic Stem Cell

描述（由申请人提供）：骨髓基质微环境是控制造血干细胞（HSC）所必需的复杂细胞网络，造血干细胞是在个体一生中产生所有血细胞谱系的原始细胞。在骨髓中，发现HSC与成骨细胞紧密接近，成骨细胞是骨中甲状旁腺激素（PTH）的主要靶点，通过激活PTH/PTHrP受体（PPR）。HSC生态位细胞成分的定义和它们影响HSC行为的机制一直很困难。最近的研究表明，成骨细胞在HSC调控中起着至关重要的作用，成骨细胞PPR激活可扩增HSC。我们已经使用PTH治疗的小鼠以及转基因小鼠，其中组成型活性PPR靶向成骨细胞（col 1-caPPR），以显示成骨细胞中PPR通过Jagged 1-Notch信号传导的激活使造血干细胞数量加倍。因此，本提案的主要目标是确定成骨细胞Jagged 1在PPR介导的HSC扩张中的功能。我们假设成骨细胞Jagged 1的表达是必要的PPR依赖的HSC扩张，它是在扩大成骨细胞，最好的支持HSC的特定亚群的工具。这些假设将通过设计用于以下目的的实验进行检验：1）描述PPR依赖性基质成骨细胞Jagged 1表达; 2）确定PPR介导的HSC扩增是否受成骨细胞Jagged 1控制; 3）确定Notch信号传导对HSC微环境的影响。这些研究将确定PTH依赖性Jagged 1和Notch信号在HSC生态位中的作用，促进对HSC自我更新的骨髓微环境控制的基本机制的理解，并为开发新方法以促进HSC扩增提供基础，目的是改善骨髓移植和骨髓衰竭状态的临床恢复。

DESCRIPTION (provided by applicant): The bone marrow stromal microenvironment is a complex cellular network essential for the control of hematopoietic stem cells (HSC), primitive cells giving rise to all blood cell lineages throughout the life of an individual. In the bone marrow, HSC are found in close proximity to osteoblasts, bone-forming cells which are the main target of parathyroid hormone (PTH) in bone, through activation of the PTH/PTHrP receptor (PPR). Definition of HSC niche cellular components and of the mechanisms by which they influence HSC behavior has been difficult. Recent studies have shown that osteoblastic cells play a crucial role in HSC regulation and that osteoblastic PPR activation expands HSC. We have used PTH-treated mice as well as transgenic mice in which a constitutively active PPR is targeted to osteoblastic cells (col1-caPPR) to show that activation of the PPR in osteoblastic cells through Jagged1-Notch signaling doubles hematopoietic stem cell numbers. The primary goal of this proposal is therefore to determine the function of osteoblastic Jagged1 in PPR-mediated HSC expansion. We hypothesize that osteoblastic Jagged1 expression is necessary for PPR-depended HSC expansion, and that it is instrumental in expanding a specific subpopulation of osteoblastic cells, which best support HSC. These hypotheses will be examined through experiments designed to: 1) delineate PPR-dependent stromal osteoblastic Jagged1 expression; 2) determine whether PPR-mediated HSC expansion is controlled by osteoblastic Jagged1; and 3) define the effects of Notch signaling on the HSC microenvironment. These studies will determine the role of PTH-dependent Jagged1 and Notch signaling in the HSC niche, advance the understanding the basic mechanisms underlying the bone marrow microenvironmental control of HSC self-renewal, and provide the basis for developing novel approaches to facilitate HSC expansion, with the goal of improving clinical recovery from bone marrow transplantation and bone marrow failure states.