ENHANCEMENT OF STEM CELL ENGRAFTMENT AND IMMUNE RECOVERY FOLLOWING HEMATOPOIETIC

Massachusetts General Hospital, Boston MA

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Abstract

This project is based on a recent observation that osteoblasts are a regulatory component of the[unreadable] hematopoietic stem cell niche and can be targeted as a means to increase stem cell numbers. Activation of[unreadable] the parathyroid hormone (PTH)/parathyroid related hormone receptor (PPR) resulted in Notch pathway[unreadable] activation and thereby expansion of hematopoietic stem cells in a mouse model. This was accompanied by a[unreadable] marked improvement in animal survival following bone marrow transplantation with limiting numbers of[unreadable] hematopoietic stem cells. This project will assess the potential for extending this model to a clinical context[unreadable] by pursuing the following specific aims:[unreadable] Aim 1: Define whether stimulation of the stem cell niche with PTH can result in improved donor stem cell[unreadable] harvests.[unreadable] Aim 2: Determine if manipulation of the graft or niche can affect the kinetics of immune recovery.[unreadable] Aim 3: Determine if ex vivo manipulation of the graft and the niche can synergistically increase stem cell[unreadable] engraftment efficiency.[unreadable] Accomplishment of these aims depends upon the clinical and large animal components of this Program[unreadable] Project and would not be achievable without the PO1 mechanism. Successful completion of this project will[unreadable] provide critical information about the value of using PTH specifically and targeting the stem cell niche more[unreadable] generally in stem cell based therapies for human disease.