Biomechanical Determinants of Hematopoietic Stem Cell Potential

造血干细胞潜力的生物力学决定因素

• 批准号: 9919750
• 负责人: PAMELA LYNN WENZEL
• 金额: $ 4.35万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-01-15 至 2022-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9919750
• 关键词: Adult; Aging; Allogenic; Aorta; Arterial Lines; Autophagocytosis; Bioenergetics; Biogenesis; Biomechanics; Biophysics; Blood Vessels; Blood flow; Bone Marrow; CREB1 gene; Calcium; Cardiac; Cell Survival; Cells; Chemicals; Clinical; Coculture Techniques; Cues; Custom; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; DNA Damage; Data; Derivation procedure; Development; Dinoprostone; Disease model; Embryo; Embryonic Development; Endothelial Cells; Energy Metabolism; Engineering; Engraftment; Environment; Fatty Acids; Generations; Genetic; Goals; Gonadal structure; Hematologic Neoplasms; Hematological Disease; Hematopoiesis; Hematopoietic; Hematopoietic Stem Cell Specification; Hematopoietic Stem Cell Transplantation; Hematopoietic stem cells; Human; Impairment; In Vitro; Interruption; Knowledge; Link; Liquid substance; Membrane Potentials; Mesonephric structure; Metabolic; Metabolism; Methods; Mitochondria; Modeling; Mus; Nitric Oxide; Outcome; Oxidative Phosphorylation; Pathway interactions; Patients; Pharmacology; Physiological; Play; Pluripotent Stem Cells; Production; Quality Control; RNA; Regulation; Reporter; Research; Role; SIRT1 gene; Signal Transduction; Source; Specific qualifier value; Stem cells; Testing; Therapeutic; To specify; Transplant-Related Disorder; Transplantation; Umbilical Cord Blood; Vascular Endothelial Cell; Virus Integration; blood treatment; cell motility; experimental study; fitness; gain of function; hematopoietic differentiation; hematopoietic gene; hematopoietic stem cell emergence; hematopoietic stem cell expansion; hematopoietic stem cell fate; hematopoietic stem cell niche; hemodynamics; hemogenic endothelium; improved; in vivo; insight; knock-down; mechanotransduction; mouse model; mutant; novel; peripheral blood; progenitor; programs; reconstitution; recruit; response; self-renewal; shear stress; stem cell fate specification; stem cell therapy; success; transcriptome

PROJECT SUMMARY For several decades, clinical outcomes of allogeneic hematopoietic stem cell (HSC) transplantation have been limited by the availability of donor-matched sources of HSCs. This has motivated global improvements in donor recruitment and matching, as well as aggressive pursuit of new strategies for development of patient-derived or universally compatible hematopoietic cells. Attempts to specify human HSCs have only produced progenitors with limited lineage and engraftment potential using co-culture and expression of hematopoietic genes through modified RNAs or viral integration. Our studies show that biomechanical force caused by flow of blood through the vasculature is a critical regulator of hematopoiesis and can promote engraftment of cells with long-term hematopoietic reconstitution potential. A number of well-characterized pathways are activated by fluid shear stress in adult vascular endothelial cells, yet little is known about signaling within hemogenic endothelial cells and their precursors in embryogenesis. Our preliminary data strongly implicates initiation of blood flow as a critical determinant of energy metabolism and mitochondrial dynamics in the HSC precursor known as the hemogenic endothelium. The objective of our research is to define signaling mechanisms triggered by biomechanical force that promote definitive hematopoiesis, with the long-term goal of exploiting biophysical cues such as shear stress in directed differentiation and expansion of customized HSCs for therapeutic transplant and blood disease modeling. Specifically, we aim to identify mitochondrial adaptations induced by vascular force that promote expansion of hemogenic endothelium via utilization of reporter mouse models of HSC emergence and mitochondrial dynamics. We will identify mitochondrial features that contribute to fate selection and survival of cells with HSC potential using murine embryos and differentiation cultures of pluripotent stem cells. We will interrogate and define the intracellular signaling that drives mitochondrial remodeling in response to physiologic intensities of fluid force in hemogenic endothelium by pharmacological and genetic targeting. Further, consequences of disrupted or enhanced mitochondrial capacity will be defined during hemogenic endothelial cell fate selection and into adulthood to reveal how mitochondrial dynamics impact the hematopoietic program at its earliest stages within the vasculature. The proposed study promises to fill a major gap in our knowledge of how newly specified HSCs and their precursors produce energy and manage metabolic processes, and will provide insight into novel methods for engineering competitive self-renewing HSCs through manipulation of metabolism.

项目摘要 几十年来，异基因造血干细胞（HSC）移植的临床结果已经被证实是不稳定的。 受供体匹配的HSC来源的可用性的限制。这促使全球改善了捐助方的工作， 招募和匹配，以及积极寻求新的策略，以开发患者源性或 普遍兼容的造血细胞试图指定人类HSC只产生祖细胞 具有有限的谱系和移植潜力，使用共培养和通过以下方式表达造血基因： 修饰的RNA或病毒整合。 我们的研究表明，由血液流过血管系统引起的生物力学力是一个关键的调节器 并可促进具有长期造血重建潜力的细胞的植入。一 在成体血管内皮细胞中，流体切应力激活了许多特征明确的途径，但 对胚胎发生中生血内皮细胞及其前体细胞内的信号传导知之甚少。我们 初步数据强烈暗示血流的启动是能量代谢的关键决定因素， HSC前体中的线粒体动力学称为生血内皮。 我们研究的目的是确定由生物力学力触发的信号机制， 明确的造血，长期目标是利用生物物理线索，如剪切应力在定向 用于治疗性移植和血液疾病建模的定制HSC的分化和扩增。 具体地说，我们的目标是确定由血管力诱导的线粒体适应，这些适应促进血管扩张。 通过利用HSC出现和线粒体动力学报告小鼠模型观察生血内皮。 我们将确定线粒体功能，有助于命运选择和生存的细胞与HSC的潜力 使用小鼠胚胎和多能干细胞的分化培养物。我们将审问并定义 细胞内信号传导驱动线粒体重塑以响应流体力的生理强度， 通过药理学和遗传学靶向造血内皮。此外，中断或 增强的线粒体能力将在生血内皮细胞命运选择期间被定义， 成年期，以揭示线粒体动力学如何影响造血程序在其最早阶段， 血管系统这项拟议的研究有望填补我们对新指定的HSC如何 及其前体产生能量并管理代谢过程，并将为新的 通过操纵代谢来工程化竞争性自我更新HSC的方法。