Biomechanical Determinants of Hematopoietic Stem Cell Potential

造血干细胞潜力的生物力学决定因素

基本信息

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
项目类别：
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

项目摘要

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.

项目概要几十年来，同种异体造血干细胞（HSC）移植的临床效果一直在改善。受限于 HSC 捐赠者匹配来源的可用性。这推动了捐助者的全球改善招募和匹配，以及积极追求开发源自患者或患者的新策略普遍相容的造血细胞。指定人类造血干细胞的尝试仅产生了祖细胞通过共培养和表达造血基因，谱系和植入潜力有限修饰的 RNA 或病毒整合。我们的研究表明，血液流经脉管系统引起的生物力学力是一个关键的调节器促进造血功能，并能促进具有长期造血重建潜力的细胞的植入。一个成体血管内皮细胞中的流体剪切应力激活了许多特征明确的通路，但关于胚胎发生中的造血内皮细胞及其前体细胞内的信号传导知之甚少。我们的初步数据强烈表明血流的启动是能量代谢的关键决定因素 HSC 前体（称为造血内皮细胞）中的线粒体动力学。我们研究的目的是定义由生物力学触发的信号机制，促进确定的造血作用，其长期目标是利用生物物理线索，例如定向定向的剪切应力用于治疗性移植和血液疾病建模的定制 HSC 的分化和扩增。具体来说，我们的目标是确定由血管力诱导的线粒体适应，从而促进扩张通过利用 HSC 出现和线粒体动力学的报告小鼠模型来研究造血内皮细胞。我们将确定有助于具有 HSC 潜力的细胞的命运选择和存活的线粒体特征使用小鼠胚胎和多能干细胞的分化培养物。我们将询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靶向的造血内皮细胞。此外，中断或增强的线粒体能力将在造血内皮细胞命运选择过程中定义并进入成年期揭示线粒体动力学如何影响造血程序的最早阶段脉管系统。拟议的研究有望填补我们对新指定的 HSC 如何进行了解的重大空白及其前体产生能量并管理代谢过程，并将提供新的见解通过操纵代谢来设计竞争性自我更新 HSC 的方法。