Role of PGE2 and other eicosanoids in hematopoietic stem cell function

 说明(申请人提供)：终生的血细胞生产是由造血干细胞(HSC)维持的，它可以自我更新并产生成熟的血细胞，以满足正常的生理要求，并响应应对压力或损伤而增加生产的需要。造血干细胞和血统受限的祖细胞(HPC)存在于骨髓微环境或微环境中，其中非造血系基质细胞在决定其保留、命运、运输和功能方面起着关键作用。虽然支持干细胞功能的造血微环境已经知道40年了，但直到最近才开始鉴定有助于HSC/HPC功能的特定细胞群体，并且关于生态位组成和细胞贡献存在争议。尽管取得了进展，但对于促进生态位调控的细胞或分子途径，关于生态位内或生态位之间的调控功能，以及生态位细胞如何在动态平衡或对压力或疾病做出反应时对HSC功能进行差异化调控，人们仍然知之甚少。长期以来，我们一直对前列腺素E2(PGE2)和环氧合酶(COX)途径在造血中的作用感兴趣，并在理解PGE2如何调控正常和异常造血方面取得了许多概念性进展。我们最近证明PGE2通过调节归巢和自我更新以及识别分子通路和药物来微调这些作用来影响HSC的功能，这促进了目前PGE2促进HSC移植的临床试验。我们最近发现，使用非类固醇抗炎药(NSAIDs)阻断通过EP4受体的PGE2信号导致HPC和HSC的不同转运，特别是具有增强植入潜力的HSC。这一发现具有重要意义，因为它强调了PGE2/COX通路在生态位中对HSC/HPC功能的重要性；确定了EP4信号通路作为探针来研究生态位功能的差异运输和异质性；并验证了生态位作为药理靶点的重要性。我们认为这个调控信号轴值得进一步探索，但更重要的是，我们相信在利基内探索PGE2-EP4信号的发现努力提供了帮助描绘特定利基成分的机会，阐明了当前有争议的话题，并提供了潜在的新的临床翻译机会。在这项建议中，我们将利用EP4受体作为分子探针来测试PGE2的假设，PGE2在一个或多个细胞壁龛/壁细胞中发出信号，关键和 不同地调节基质微环境，影响HSC和HPC在动态平衡和对急性和慢性应激的运输(保留、外流和功能(归巢、植入))。了解骨髓间充质干细胞和造血祖细胞转运和功能所涉及的细胞和旁分泌的相互作用，对于为挽救生命的造血移植和清髓疗法治疗各种癌症收集细胞具有重要意义。由于非甾体抗炎药通过所有4种EP受体阻断信号，了解EP4信号的确切作用将很可能确定更具选择性和有效的治疗策略。

 DESCRIPTION (provided by applicant): Lifelong blood cell production is maintained by hematopoietic stem cells (HSC) that self-renew as well as produce mature blood cells to meet normal physiologic requirements and respond to needs for increased production in response to stress or injury. HSC and lineage restricted progenitor cells (HPC) reside associated with bone marrow microenvirons or niches where non-hematopoietic stromal cells play key roles in determining their retention, fate, trafficking, and function. While hematopoietic microenvironments supporting stem cell function have been known for 40 years, specific populations of cells that contribute to HSC/HPC function have only recently begun to be identified, and controversy exists regarding niche composition and cell contribution. Despite advances, little is still known about cellular or molecular pathways contributing to niche regulation, about regulatory functions within or between niches, and how niche cells differentially regulate HSC functions under homeostasis or in response to stress or disease. We have had a long standing interest in the roles of prostaglandin E2 (PGE2) and the cyclooxygenase (COX) pathway on hematopoiesis and have made numerous conceptual advancements to the understanding of how PGE2 regulates normal and abnormal hematopoiesis. Our recent demonstration that PGE2 affects HSC function through regulation of homing and self-renewal and identification of molecular pathways and agents to fine tuning these effects, has facilitated current clinical testing of PGE2 to enhance HSC transplant. We recently found that blocking PGE2 signaling through the EP4 receptor using non-steroidal anti-inflammatory drugs (NSAIDs) results in differential HPC and HSC trafficking, particularly of HSC with enhanced engraftment potential. This finding is significant in that it highlights the importance of the PGE2 /COX pathway in the niche on HSC/HPC function; identifies the EP4 signaling pathway as a probe to investigate differential trafficking and heterogeneity of niche function; and validates the niche as a pharmacologic target. We believe this regulatory signaling axis is worth further exploration, but more importantly we believe discovery efforts exploring PGE2-EP4 signaling within the niche offer the opportunity to help delineate specific niche components, shed light on a current controversial topic and offers potential new clinical translation opportunities. In this proposal we will utilize the EP4 receptor as a molecular probe t test the hypothesis that PGE2, signaling in one or more cellular niches/niche cells, critically and differentially regulates stromal microenvirons, influencing both the trafficking (retention, egress and function (homing, engraftment) of HSC and HPC at homeostasis and in response to acute and chronic stress. Understanding cellular and paracrine interactions within marrow niches involved in HSC and HPC trafficking and function has major implications for collection of cells for lifesaving hematopoietic transplantation and treatment of various cancers with myeloablative therapies. Since NSAIDs block signaling through all 4 EP receptors, understanding the precise role of EP4 signaling will very likely identify more selective and efficacious therapeutic strategies.