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: 10930184
• 负责人: Owen James Tamplin
• 金额: $ 53.76万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-06-20 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10930184
• 关键词: ATAC-seq; Address; Adult; Aorta; Area; Behavior; Binding; Biological Models; Blood Vessels; Bone Marrow; Bypass; Cell Adhesion; Cell Adhesion Molecules; Cell Communication; Cell Differentiation process; Cell Maturation; Cell Ontogeny; Cell Therapy; Cells; Chromatin; Circulation; Clinical; Coculture Techniques; Complex; Data; Derivation procedure; Development; Dorsal; Electron Microscopy; Embryo; Endothelial Cells; Engraftment; Erythro; Event; Extracellular Matrix; Fetal Liver; Genetic; Goals; Growth; Hematological Disease; Hematology; Hematopoiesis; Hematopoietic Neoplasms; Hematopoietic stem cells; Human; Image; In Vitro; Integrin alpha Chains; Integrins; Investigation; Kidney; Knowledge; Mammals; Marrow; Mediating; Methods; Modeling; Mus; Myelogenous; Non-Malignant; PIK3CG gene; Pathway interactions; Patient-Focused Outcomes; Patients; Phenotype; Population; Positioning Attribute; Procedures; Process; Protocols documentation; Research; Research Proposals; Role; SU 5416; Signal Transduction; Signaling Molecule; Specific qualifier value; Stem cell transplant; Testing; Therapeutic; Tissues; Translating; Transplantation; Travel; Up-Regulation; Vascular Endothelial Growth Factor C; Vascular Endothelial Growth Factors; Vertebrates; Zebrafish; cell behavior; cell motility; cell type; curative treatments; fetal; genetic signature; hematopoietic differentiation; hematopoietic tissue; hematopoietic transplantation; hemogenic endothelium; improved; improved outcome; in vivo; inhibitor; innovation; knock-down; light microscopy; live cell imaging; loss of function; lymphatic development; lymphatic vessel; migration; mouse model; mutant; novel; progenitor; programs; receptor; response; single-cell RNA sequencing; small molecule; stem cells; tool

PROJECT SUMMARY/ABSTRACT Hematopoietic stem and progenitor cell (HSPC) 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. HSPCs reside in a microenvironment surrounded by niche cells that help regulate their function. Our research proposal seeks to address fundamental questions regarding the cellular interactions between HSPCs and niche cells. During development in the embryo, HSPCs move through different tissues and have changing requirements for contact with the microenvironment. HSPCs first arise in the dorsal aorta, a large vessel in the embryo, and are then released into circulation. Next, HSPCs migrate to the fetal liver where the population of cells expands exponentially via symmetric divisions. Finally, HSPCs migrate again to colonize the bone marrow where they will remain throughout adulthood. As HSPCs are migrating between these different hematopoietic tissues, they are also becoming more mature and are programmed towards their adult quiescent state. We use zebrafish and mice as model systems that are highly conserved with humans and have many genetic tools for functional testing and live imaging of cellular behaviors. In zebrafish, we have found a novel role for vascular endothelial growth factor c (vegfc) in the release of HSPCs from the dorsal aorta. Vegfc also regulates a fate decision in pre-HSPCs that determines if they will become a stem cell or a different type of progenitor cell. At later stages, we found a programming function for integrin alpha 4 (itga4) in the caudal hematopoietic tissue (CHT), the zebrafish equivalent of the fetal liver. We hypothesize that the timing of HSPC contact and transitions between developmental niches is critical for their correct programming. We will address this hypothesis through the following Specific Aims: 1) Define the role of vegfc in HSPC transition and release from the dorsal aorta. 2) Determine how itga4-dependent contact with the CHT niche programs HSPCs as they transition from fetal-like to adult stages. We will perform in vivo genetic knockdown and small molecule treatments, together with live imaging, to understand the dynamic interactions between HSPCs and niche cells. We will then translate these results to an in vitro vascular niche that is used to differentiate cells into transplantable HSPCs that could lead to cell-based therapies for patients.

项目概要/摘要 造血干细胞和祖细胞（HSPC）移植是许多血液疾病的治疗方法 和癌症。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。 HSPC 存在于微环境中，周围有微环境细胞，有助于调节其功能。我们的研究 该提案旨在解决有关 HSPC 和利基之间细胞相互作用的基本问题 细胞。在胚胎发育过程中，HSPC 穿过不同的组织并发生变化 与微环境接触的要求。 HSPC 首先出现在背主动脉，背主动脉是大脑中的一条大血管。 胚胎，然后释放进入循环系统。接下来，HSPC 迁移到胎儿肝脏，其中 细胞通过对称分裂呈指数增长。最后，HSPC 再次迁移并定植于骨髓 他们将一直呆在这个地方直到成年。由于 HSPC 在这些不同的造血系统之间迁移 随着组织的不断成熟，它们也变得更加成熟，并被编程为进入成年静止状态。我们使用 斑马鱼和小鼠作为模型系统，与人类高度保守，并且拥有许多遗传工具 细胞行为的功能测试和实时成像。在斑马鱼中，我们发现了血管的新作用 内皮生长因子 c (vegfc) 参与背主动脉 HSPC 的释放。 Vegfc 还调节命运 前 HSPC 中的决定决定它们是否会成为干细胞或不同类型的祖细胞。在 后期，我们在尾部造血组织中发现了整合素α4（itga4）的编程功能 (CHT)，相当于斑马鱼的胎儿肝脏。我们假设 HSPC 接触和转换的时间 发展利基之间的关系对于他们的正确编程至关重要。我们将通过以下方式解决这个假设 以下具体目标： 1) 定义 vegfc 在 HSPC 转换和从背侧释放中的作用 主动脉。 2) 确定 itga4 依赖的与 CHT 利基的接触如何在 HSPC 转变时对其进行编程 从胎儿阶段到成年阶段。我们将进行体内基因敲除和小分子治疗， 结合实时成像，了解 HSPC 和利基细胞之间的动态相互作用。我们随后将 将这些结果转化为体外血管生态位，用于将细胞分化为可移植的 HSPC 这可能会为患者带来基于细胞的疗法。