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.

项目概要 该提案的目标是开发一种模型技术，能够对脂肪进行临床前研究 随着时间的推移，真实灌注微血管网络环境中的衍生基质血管分数（SVF） 几天的过程。这样的模型并不存在。 SVF移植是一种有前景的新疗法 基于 SVF 可以形成新血管的理念，其应用范围涵盖从心脏缺血到组织修复。 关于新生血管生长（即新血管形成）的时间过程仍然存在巨大的知识差距， SVF 衍生血管与附近微血管网络的整合，以及新血管的细胞组成 船只。了解 SVF 细胞在何处以及如何促进微血管生长将有助于指导他们 治疗用途。 PI 的实验室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的细胞动态 网络。这种仿生“观点”导致了与内皮细胞动力学和 淋巴/血管可塑性。 PI的实验室还开发了一种用于引入灌注的生物反应器 在培养的微血管网络中，现在具有独特的地位，可以将这些方法与 鼠组织开发一种评估 SVF 命运和功能的全新技术（图 1）。 SVF 疗法尚未发挥其潜力。我们新颖的高内涵工具将支持多单元/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 影响。根据 NHLBI 特别关注通知的目的，目标是发展和 以产生新假设为目标的发现驱动。 目标 1：发现 SVF 命运和功能的模型开发 – 将生物反应器设计与 组织培养建立灌注微血管网络模型以评估 SVF 新血管形成。 目标 2：对假设生成项目的影响 – 确定神经元胶质抗原 2 的影响 (NG2) 对 SVF 新生血管形成的抑制。 拟议的研究将为发现 SVF 动力学和效应提供新的“观点” 生理相关的微血管环境，具有其他模型无法读取的读数。长期来看 这项工作的目的是了解和评估潜在的 SVF 疗法。该提案将展示 仿生平台对于基础科学研究的价值，重点是识别 SVF 动力学并阐明 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)