Modulating endothelial-specific signaling to enhance functional hematopoiesis.

成体造血干细胞（HSC）的定义是它们进行自我更新的能力， 维持在血液和免疫系统中产生所有类型成熟造血细胞的能力。 系统骨髓（BM）微环境提供关键的促造血信号， 维持造血系统。了解这些信号可能会导致发展 新的策略，以增加HSC的数量，将可在临床环境中治疗 多种血液病。本研究项目的总体目标是通过以下方式定义机制： 其中BM血管龛中的NF-kB信号调节HSC池的维持， 自我平衡和再生条件。我们最近已经证明，内皮细胞（EC）发挥作用， 通过激活Akt通路维持HSC稳态的重要作用，使EC能够 维持和扩增功能性HSC。然而，Akt下游的信号通路负责 赋予EC调控HSC自我更新和分化的指导能力， 未知我们已经发现，抑制Akt激活的EC中的NF-κ B信号传导导致了鲁棒的细胞凋亡。 扩增功能性小鼠HSC，从而增强造血恢复， 骨髓抑制，部分通过保护BM微环境。根据这些观察，我们 假设抑制BMEC中的NF-κ B信号通路调节BMEC的维持， 通过保护造血和血管系统免受辐射诱导的DNA的影响， 代谢损伤为了研究NF-kB信号在BMEC中的作用，我们将使用转基因小鼠模型， 其中NF-kB信号传导在血管特异性启动子的控制下被抑制。利用新 我们实验室开发的技术使我们能够从BM中分离和培养EC，我们将 能够测试是否抑制血管龛内的Akt/NF-kB信号传导轴1）保护HSC免受 辐射引起的DNA和细胞损伤，2）有助于维持和恢复适当的代谢特征 在造血再生过程中，3）通过以下方式使BM血管生态位和造血系统恢复活力： 移植适当活化的BMEC，以及4）增强新的促造血因子的表达 促进体内平衡和再生造血。这些研究将开始揭开 EC支持HSC自我更新和分化之间平衡的机制。这些 研究将为开发旨在恢复HSC生态位的新治疗策略奠定基础 以及在清髓性治疗后恢复造血区室。

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.