Modulating endothelial-specific signaling to enhance functional hematopoiesis.

成人造血干细胞(HSCs)的定义是其经历自我更新和 保持在血液和免疫系统内生成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，调节 维持造血系统。理解这些信号可能会导致 的新策略，以增加可在临床环境中使用的造血干细胞数量，以治疗 各种各样的血液病。该研究项目的总体目标是通过以下方式定义机制 BM血管壁龛中的哪个核因子-kB信号调节HSC池的维持 动态平衡和再生条件。我们最近证明了内皮细胞(ECs)在 通过激活Akt通路在维持HSC动态平衡方面发挥重要作用，使ECs能够 维护和扩展功能性HSC。然而，Akt下游的信号通路负责 赋予内皮细胞调节造血干细胞自我更新和分化的指导能力 未知。我们发现，抑制Akt激活的内皮细胞中的NF-kB信号导致了 扩增有功能的小鼠造血干细胞，从而促进移植后的造血恢复 骨髓抑制，部分是通过保护骨髓微环境来实现的。基于这些观察，我们 假设抑制BMECs中的核因子-kB信号通路调节维持 通过保护造血和血管系统免受辐射诱导的DNA和 代谢损伤。为了研究核因子-kB信号在骨髓间充质干细胞中的作用，我们将使用转基因小鼠模型 其中，在血管特异性启动子的控制下，核因子-kB信号被抑制。利用小说 我们实验室开发的技术使我们能够从骨髓中分离和培养内皮细胞，我们将 能够测试在血管巢内抑制Akt/NF-kB信号轴是否保护HSC 辐射诱导的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)通过以下方式恢复骨髓血管壁龛和造血系统的活力 移植适当活化的骨髓内皮细胞，以及4)增强新的促造血因子的表达 促进动态平衡和再生造血的物质。这些研究将开始揭开 ECs支持HSC自我更新和分化之间的平衡的机制。这些 研究将为开发旨在恢复HSC利基的新治疗策略奠定基础 以及在清髓治疗后恢复造血室。

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.