Osteoblastic Activation in the Hematopoietic Stem Cell

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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.