Identification of biomechanical pathways that promote hematopoiesis

促进造血的生物力学途径的鉴定

• 批准号: 8842626
• 负责人: PAMELA LYNN WENZEL
• 金额: $ 14.16万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-15 至 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8842626
• 关键词: Ablation; Adult; Advisory Committees; Agonist; Anemia; Aorta; Biochemical; Biological Assay; Biomechanics; Blood; Blood flow; Boston; Cell Lineage; Cell surface; Cells; Childhood; Clinical; Critical Pathways; Data; Development; Dorsal; Educational process of instructing; Embryo; Embryonic Development; Endothelial Cells; Endothelium; Engraftment; Flow Cytometry; Friction; Gene Expression; Genetic; Genetically Engineered Mouse; Green Fluorescent Proteins; Hematologic Neoplasms; Hematological Disease; Hematology; Hematopoiesis; Hematopoietic; Hematopoietic Stem Cell Transplantation; Hematopoietic stem cells; Infection; International; Life; Liquid substance; Lymphoid; Marrow; Mechanical Stress; Mechanics; Mediating; Medical center; Mentors; Mentorship; Mouse Strains; Mus; Nature; Pathway interactions; Patients; Pediatric Hospitals; Phenotype; Play; Population; Post-Translational Protein Processing; Regulation; Reporter; Research; Research Design; Research Institute; Risk; Role; Signal Pathway; Signal Transduction; Source; Staging; Stem cells; Stress; Stretching; Testing; Transplantation; Ubiquitin C; Umbilical Cord Blood; Vascular Endothelium; Work; biomechanical engineering; bone marrow failure syndrome; career; defined contribution; fluid flow; genetic manipulation; graft vs host disease; hemodynamics; innovation; insight; medical schools; mimicry; morphogens; notch protein; oncology; peripheral blood; pressure; programs; promoter; response; self-renewal; shear stress; stem cell biology; stem cell therapy; success

DESCRIPTION (provided by applicant): In the midgestation embryo, blood flow begins after initiation of the heartbeat and subjects vessel walls to viscous friction, pressure, and stretching. These biomechanical forces induce morphological change and activation of differentiation programs not only in endothelial cells but also in hematopoietic cells of the dorsal aorta. The first true hematopoietic stem cells (HSCs) that arise in this region, referred to as the para-aortic splanchnopleura (PSp), are responsible for life-long hematopoiesis of all blood lineages. We have found that fluid frictional force stimulates genetic pathways critical for definitive hematopoiesis and promotes long-term engraftment in adult recipient mice when applied to PSp cells (Nature 2009, 459:1131-1135 and unpublished data). A number of well-characterized pathways are activated by fluid flow in endothelial cells, yet little is known about the signaling pathways that determine hematopoietic fate. The studies proposed herein aim to identify the mechanosensitive genetic signals that are important for hematopoietic specification and expansion. Further, I will test the ability of soluble molecules to mimic the pro-hematopoietic effects of mechanical force. These studies are designed to define the role of biomechanical stress in regulation of hematopoietic potential and promise to inspire innovative approaches for the expansion of transplantable HSCs in culture. Three aims will test the hypothesis that hematopoietic stem cell emergence and expansion is triggered by biomechanically-responsive pathways that can be stimulated by biochemical and pharmacological compounds. Aim 1. Determine the cell surface phenotype(s) of cells that respond to biomechanical forces within the PSp, the embryonic region from which the first definitive HSCs arise. Aim 2. Define and interrogate genetic pathways activated by biomechanical stimulation in hematopoietic precursors from the PSp. Aim 3. Identify pharmacologic compounds and morphogens that promote specification or expansion of HSCs by mimicry of biomechanical forces. Dr. Pamela Wenzel, a postdoctoral research fellow at Children's Hospital Boston (CHB) has outlined a 5- year career plan that will augment and strengthen her background in developmental hematopoiesis and biomechanics. Under the mentorship of Dr. George Daley, a pioneer in the field of stem cell biology, she seeks to identify the genetic mechanisms that sense and respond to biomechanical forces at the earliest stages of definitive hematopoiesis. Dr. Wenzel will be mentored by an Advisory Committee of international leaders in hematopoiesis, biomechanical engineering, and hemodynamics, including Drs. Leonard Zon, Donald Ingber, and Guillermo Garcma-Cardeqa. Finally, the proposed research will be carried out in the Division of Hematology/Oncology at Children's Hospital Boston, the world's largest research institute at a pediatric medical center and the primary pediatric teaching affiliate of Harvard Medical School.

描述(申请人提供)：在中期胚胎中，血流在心跳开始后开始，使血管壁受到粘性摩擦、压力和拉伸。这些生物力学力量不仅诱导内皮细胞的形态改变和分化程序的激活，而且还诱导背主动脉造血细胞的形态改变和分化程序的激活。最早出现在该区域的真正的造血干细胞(HSCs)被称为腹主动脉旁内脏胸膜(PSP)，负责所有血系的终生造血。我们已经发现，当应用于PSP细胞时，流体摩擦力刺激对最终造血至关重要的遗传途径，并促进成年受体小鼠的长期植入(自然，2009,459：1131-1135和未发表的数据)。内皮细胞中的液体流动激活了许多具有良好特性的通路，但对决定造血命运的信号通路知之甚少。在此提出的研究旨在识别对造血规范和扩增重要的机械敏感遗传信号。此外，我将测试可溶性分子模拟机械力的促造血作用的能力。这些研究旨在明确生物机械应力在调节造血潜能中的作用，并有望激励创新的方法在培养中扩大可移植的HSCs。三个目标将检验这一假设，即造血干细胞的出现和扩张是由生物力学反应途径触发的，这些途径可以被生化和药物化合物刺激。目的1.确定PSP内对生物力学作用力反应的细胞表面表型(S)，PSP是第一个明确的HSC产生的胚胎区。目的2.定义和询问PSP中由生物力学刺激激活的造血祖细胞的遗传通路。目的3.通过模拟生物力学的作用，鉴定促进造血干细胞分化或扩增的药理化合物和形态因子。波士顿儿童医院(CHB)博士后研究员帕梅拉·温泽尔(Pamela Wenzel)博士概述了一项为期5年的职业计划，该计划将充实和加强她在发育造血和生物力学方面的背景。在干细胞生物学领域的先驱乔治·戴利博士的指导下，她试图确定在最终造血的最早阶段感知生物力学力量并对其做出反应的遗传机制。温泽尔博士将接受一个由造血、生物机械工程和血液动力学领域国际领袖组成的咨询委员会的指导，其中包括伦纳德·宗博士、唐纳德·英格伯博士和吉列尔莫·加尔马-卡德卡博士。最后，这项拟议的研究将在波士顿儿童医院的血液/肿瘤科进行，这是世界上最大的儿科医学中心研究机构，也是哈佛医学院的主要儿科教学附属机构。

项目成果

Biomechanical forces promote blood development through prostaglandin E2 and the cAMP-PKA signaling axis.

• DOI: 10.1084/jem.20142235
• 发表时间: 2015-05-04
• 期刊: The Journal of experimental medicine
• 作者: Diaz MF;Li N;Lee HJ;Adamo L;Evans SM;Willey HE;Arora N;Torisawa YS;Vickers DA;Morris SA;Naveiras O;Murthy SK;Ingber DE;Daley GQ;García-Cardeña G;Wenzel PL
• 通讯作者: Wenzel PL

Application of fluid mechanical force to embryonic sources of hemogenic endothelium and hematopoietic stem cells.

流体机械力在造血内皮和造血干细胞胚胎来源中的应用。

• DOI: 10.1007/7651_2014_95
• 发表时间: 2015
• 期刊: Methods in molecular biology (Clifton, N.J.)
• 作者: Li,Nan;Diaz,MiguelF;Wenzel,PamelaL
• 通讯作者: Wenzel,PamelaL

Biomechanical force in blood development: extrinsic physical cues drive pro-hematopoietic signaling.

• DOI: 10.1016/j.diff.2013.06.004
• 发表时间: 2013-10
• 期刊: DIFFERENTIATION
• 影响因子: 2.9
• 作者: Lee, Hyun Jung;Li, Nan;Evans, Siobahn M.;Diaz, Miguel F.;Wenzel, Pamela L.
• 通讯作者: Wenzel, Pamela L.

Fluid shear stress activates YAP1 to promote cancer cell motility.

流体剪切应力激活YAP1以促进癌细胞的运动。

• DOI: 10.1038/ncomms14122
• 发表时间: 2017-01-18
• 期刊: Nature communications
• 影响因子: 16.6
• 作者: Lee HJ;Diaz MF;Price KM;Ozuna JA;Zhang S;Sevick-Muraca EM;Hagan JP;Wenzel PL
• 通讯作者: Wenzel PL

Focal adhesion kinase signaling regulates anti-inflammatory function of bone marrow mesenchymal stromal cells induced by biomechanical force.

• DOI: 10.1016/j.cellsig.2017.06.012
• 发表时间: 2017-10
• 期刊: Cellular signalling
• 影响因子: 4.8
• 作者: Lee HJ;Diaz MF;Ewere A;Olson SD;Cox CS Jr;Wenzel PL
• 通讯作者: Wenzel PL