Modulating endothelial-specific signaling to enhance functional hematopoiesis.

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Adult hematopoietic stem cells (HSCs) are defined by their ability to undergo self-renewal and maintain the capacity to generate all types of mature hematopoietic cells within the blood and immune system. The bone marrow (BM) microenvironment supplies critical pro-hematopoietic signals that regulate the maintenance of the hematopoietic system. Understanding these signals may lead to the development of novel strategies to increase the number of HSCs that would be available in a clinical setting to treat a wide variety of hematological diseases. The overall goal of this research project is to define mechanisms by which NF-kB signaling in the BM vascular niche regulates the maintenance of the HSC pool during homeostatic and regenerative conditions. We have recently demonstrated that endothelial cells (ECs) play an essential role in maintaining HSC homeostasis through activation of the Akt pathway, enabling ECs to maintain and expand functional HSCs. However, the signaling pathways downstream of Akt responsible for endowing ECs with the instructional capacity to regulate the self-renewal and differentiation of HSCs are unknown. We have found that the inhibiting NF-kB signaling in Akt-activated ECs results in robust expansion of functional mouse HSCs thereby enhancing hematopoietic recovery following myelosuppression, in part, by protecting the BM microenvironment. Based on these observations, we hypothesize that the inhibition of NF-kB signaling pathway in BMECs regulates the maintenance of the HSC pool by protecting the hematopoietic and vascular system from radiation-induced DNA and metabolic damage. To study the role of NF-kB signaling in BMECs, we will use a transgenic mouse model in which NF-kB signaling is inhibited under the control of a vascular specific promoter. Utilizing novel techniques developed in our laboratory that enable us to isolate and cultivate ECs from the BM, we will be able to test if inhibiting the Akt/NF-kB signaling axis within the vascular niche 1) protects the HSC from radiation induced DNA and cellular damage, 2) helps maintain and restore the proper metabolic profile during hematopoietic regeneration, 3) rejuvenates the BM vascular niche and hematopoietic system by transplanting properly activated BMECs, and 4) enhances the expression of novel pro-hematopoietic factors that promote homeostatic and regenerative hematopoiesis. These studies will begin to unravel the mechanisms by which ECs support the balance between HSC self-renewal and differentiation. These studies will lay the foundation to develop new therapeutic strategies aimed at rejuvenating the HSC niche and restoring the hematopoietic compartment following myeloablative treatments.