Improving the interaction of hematopoietic stem cells with the perivascular niche to promote engraftment

改善造血干细胞与血管周围微环境的相互作用以促进植入

• 批准号: 10240737
• 负责人: Owen James Tamplin
• 金额: $ 47.47万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-01 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10240737
• 关键词: Address; Adhesives; Beds; Blood Vessels; Bone Marrow; Cells; Cellular Structures; Clinical; Coculture Techniques; Complex; Concept Formation; Cues; Data; Discontinuous Capillary; Electron Microscopy; Endothelial Cells; Engraftment; Feedback; Fetal Liver; Genetic; Genetic study; Goals; Hematological Disease; Hematopoiesis; Hematopoietic Neoplasms; Hematopoietic Stem Cell Transplantation; Hematopoietic stem cells; Image; Imaging technology; In Vitro; Instruction; Integrins; KDR gene; Kidney; Mammals; Marrow; Mediating; Mediator of activation protein; Microscopy; Modeling; Molecular; Paracrine Communication; Patient-Focused Outcomes; Procedures; Process; Protocols documentation; Research Proposals; Role; SU 5416; Seminal; Signal Transduction; Site; Speed; Stem cell transplant; Structure; System; Testing; Translating; Transplantation; Vascular Cell Adhesion Molecule-1; Vascular Endothelial Growth Factor C; Vascular Endothelial Growth Factors; Zebrafish; arteriole; base; bone; cell type; curative treatments; endothelial stem cell; fetal; hematopoietic stem cell expansion; hematopoietic stem cell fate; hematopoietic stem cell niche; hematopoietic tissue; high resolution imaging; imaging modality; improved; in vivo; inhibitor/antagonist; insight; knock-down; light microscopy; mutant; novel; programs; residence; small molecule; stem cells

PROJECT SUMMARY/ABSTRACT Hematopoietic stem cell (HSC) transplantation is a curative treatment for many blood diseases and cancers. However, these procedures still need to be optimized to improve patient outcomes and survival. In part, we have been limited by our poor understanding of how donor HSCs interact with the recipient bone marrow after transplantation. This research proposal seeks to address fundamental questions regarding the cellular interactions between HSCs and niche cells. Based on our previous data, we have shown that the niche not only instructs HSC, but that HSC also transmit instructive cues to the niche. These include triggered remodeling of surrounding endothelial cells into a supportive pocket that “cuddles” the HSC. To better describe this novel cellular structure, we combined multiple imaging modalities to produce the first correlative light and electron microscopy data of an endogenous stem cell in its niche. We have since performed functional genetic studies that provided mechanistic insight into the formation of this structure. These preliminary results have led us to pursue the following Specific Aims: 1) Identify the HSC-derived paracrine signals that mediate EC remodeling to form a niche for HSCs; 2) Identify mechanisms of adhesive HSC-EC niche interactions that promote signaling and stable expansion of the HSC pool. We will perform in vivo genetic knockdown and small molecule treatments, together with live imaging, to understand the dynamic interactions between HSC and endothelial cells. We will then translate these results to an in vitro vascular niche with the potential to expand HSCs prior to transplantation. Ultimately, we hope our studies will lead to improved clinical HSC transplantation protocols.

项目概要/摘要 造血干细胞（HSC）移植是许多血液疾病和癌症的治疗方法。 然而，这些程序仍然需要优化，以改善患者的治疗结果和生存率。在某种程度上，我们有 由于我们对供体 HSC 在移植后如何与受体骨髓相互作用了解甚少，因此受到限制 移植。该研究计划旨在解决有关细胞的基本问题 HSC 和微环境细胞之间的相互作用。根据我们之前的数据，我们已经表明，利基市场并不 只指导 HSC，但 HSC 也向利基传递指导性线索。这些包括触发 将周围的内皮细胞重塑为“拥抱”HSC 的支持性口袋。为了更好地描述 这种新颖的细胞结构，我们结合了多种成像方式来产生第一个相关光和 其生态位中内源干细胞的电子显微镜数据。此后我们进行了功能遗传 这些研究为这种结构的形成提供了机制上的见解。这些初步结果导致 我们追求以下具体目标： 1) 识别 HSC 衍生的介导 EC 的旁分泌信号 重塑 HSC 的利基市场； 2) 确定粘附 HSC-EC 生态位相互作用的机制 促进 HSC 池的信号传导和稳定扩张。我们将进行体内基因敲除 和小分子治疗，结合实时成像，以了解 HSC 之间的动态相互作用 和内皮细胞。然后，我们将把这些结果转化为具有扩展潜力的体外血管生态位 移植前的 HSC。最终，我们希望我们的研究能够改善临床 HSC 移植 协议。