Bioengineering Approach for Advancing Reparative Medicine Stem Cell Technologies

推进修复医学干细胞技术的生物工程方法

• 批准号: 10673032
• 负责人: WALTER L MURFEE
• 金额: $ 18.18万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10673032
• 关键词: Adipose tissue; Adult; Attention; Basic Science; Biological Models; Biomedical Engineering; Biomimetics; Bioreactors; Blood; Blood Vessels; CSPG4 gene; Cell Fraction; Cells; Clinical; Development; DsRed; Endothelial Cells; Environment; Evaluation; Generations; Goals; Growth; Heart Research; Intercellular Junctions; Investigation; Knock-out; Knowledge; Laboratories; LoxP-flanked allele; Lung; Lymphangiogenesis; Lymphatic; Modeling; Mus; Myocardial Ischemia; National Heart, Lung, and Blood Institute; Perfusion; Pericytes; Permeability; Physiological; Population; Positioning Attribute; Rattus; Research; Sleep Disorders; System; Technology; Therapeutic Uses; Time; Tissues; Transgenic Mice; Transplantation; Work; angiogenesis; clinical translation; density; design; ex vivo perfusion; innovation; interest; malformation; model development; molecular dynamics; neovascularization; neovasculature; network models; new technology; novel; novel therapeutics; pre-clinical; reparative medicine; stem cell technology; technology development; tissue culture; tissue repair; tool

Project Summary The goal of this proposal is to develop a model technology that enables pre-clinical investigation of adipose derived stromal vascular fraction (SVF) in a real perfused microvascular network environment over the time course of a few days. Such a model does not exist. SVF transplantation is a promising new therapy for applications spanning from cardiac ischemia to tissue repair based on the idea that SVF can form new vessels. Big knowledge gaps remain relating to the time course of the de novo vessel growth (i.e. neovascularization), the integration of SVF derived vessels with nearby microvascular networks, and the cell makeup of the new vessels. Understanding where and how SVF cells contribute to microvascular growth will help guide their therapeutic use. The PI's laboratory has developed and validated the physiological relevance of a novel rat tissue culture model that enables real-time ex vivo observation of cell dynamics in intact adult microvascular networks. This biomimetic “view” has led to discoveries related to endothelial cell dynamics and lymphatic/blood vessel plasticity. The PI's laboratory has also developed a bioreactor for introducing perfusion in the cultured microvascular networks and is now uniquely positioned to combine these approaches with murine tissue to develop a totally new technology for evaluating SVF fate and function (Figure 1). SVF therapies have not yet reached their potential. Our novel high-content tool will enable multi-cell/system readouts for angiogenesis, lymphangiogenesis, and vessel permeability that will define the scope of SVF impact. In line with the purpose of the NHLBI notice of special interest, the aims are development and discovery driven with the goal of generating new hypotheses. Aim 1: Model Development for Discovery of SVF Fate and Function – To combine bioreactor design with tissue culture to establish a perfused microvascular network model for evaluating SVF neovascularization. Aim 2: Impact for Hypothesis Generation Projects – To determine the impact of neuron-glial antigen 2 (NG2) inhibition on SVF neovascularization. The proposed research will offer a new “view” for the discovery of SVF dynamics and effects in a physiologically relevant microvascular milieu with readouts not possible with other models. The long-term objective of this work is to understand and evaluate potential SVF therapies. This proposal will demonstrate the value of a biomimetic platform for basic science studies focused on identifying SVF dynamics and elucidating how environmental, cellular, and specific molecular dynamics might guide SVF therapy.

项目摘要 这项提案的目标是开发一种模型技术，使临床前研究脂肪 随时间推移在真实的灌注微血管网络环境中的衍生基质血管分数（SVF） 几天的课程。这样的模式并不存在。SVF移植是一种很有前途的新疗法， 基于SVF可以形成新血管的想法，其应用范围从心脏缺血到组织修复。 与新生血管生长（即新血管形成）的时间进程相关的知识差距仍然很大， SVF衍生的血管与附近微血管网络的整合，以及新血管的细胞组成。 船舶.了解SVF细胞在哪里以及如何促进微血管生长将有助于指导他们的研究。 治疗用途。PI的实验室已经开发并验证了一种新型大鼠的生理相关性， 组织培养模型，能够实时离体观察完整成人微血管中的细胞动力学 网络.这种仿生“观点”导致了与内皮细胞动力学相关的发现， 淋巴/血管可塑性。PI的实验室还开发了一种生物反应器，用于引入灌注 在培养的微血管网络，现在是独特的定位，联合收割机结合这些方法， 小鼠组织中，以开发一种全新的技术，用于评估SVF的命运和功能（图1）。SVF 治疗尚未发挥其潜力。我们的新型高内容工具将使多细胞/系统 血管生成、淋巴管生成和血管通透性的读数，将定义SVF的范围 冲击根据NHLBI特别关注通知的目的，其目标是发展和 以产生新假设为目标的发现驱动。 目的1：用于发现SVF命运和功能的模型开发-将联合收割机生物反应器设计与 组织培养建立评价SVF的灌注微血管网络模型 新生血管形成 目的2：对假设生成项目的影响-确定神经胶质抗原2的影响 (NG2)抑制SVF新生血管形成。 这项研究将为发现SVF的动力学和效应提供一个新的“视角”， 生理相关的微血管环境，其他模型无法读出。长期 这项工作的目的是了解和评估潜在的SVF治疗。该提案将展示 仿生平台对基础科学研究的价值，重点是识别SVF动力学和阐明 环境、细胞和特定分子动力学如何指导SVF治疗。

项目成果

Estimation of shear stress heterogeneity along capillary segments in angiogenic rat mesenteric microvascular networks.

估计血管生成大鼠肠系膜微血管网络中沿毛细血管段的剪切应力异质性。

• DOI: 10.1111/micc.12830
• 发表时间: 2023
• 期刊: Microcirculation (New York, N.Y. : 1994)
• 作者: Hu,Nien-Wen;Lomel,BanksM;Rice,ElijahW;Hossain,MirMdNasim;Sarntinoranont,Malisa;Secomb,TimothyW;Murfee,WalterL;Balogh,Peter
• 通讯作者: Balogh,Peter

Angiogenic Microvascular Wall Shear Stress Patterns Revealed Through Three-dimensional Red Blood Cell Resolved Modeling.

• DOI: 10.1093/function/zqad046
• 发表时间: 2023
• 期刊: Function (Oxford, England)