The mechanics of host cell repopulation of engineered tissues

工程组织的宿主细胞再生机制

• 批准号: 10580269
• 负责人: Kristen L Billiar
• 金额: $ 42.95万
• 依托单位: WORCESTER POLYTECHNIC INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-01 至 2026-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10580269
• 关键词: 3-Dimensional; Acceleration; Adhesions; Affect; Aorta; Apoptosis; Area; Behavior; Biopolymers; Bioprosthesis device; Bioreactors; Blood Vessels; Cell-Matrix Junction; Cells; Child; Complex; Development; Educational process of instructing; Endothelial Cells; Endothelium; Environment; Exposure to; Extracellular Matrix; Fibroblasts; Frequencies; Gel; Goals; Grant; Heart Valves; Histologic; Immune response; Implant; In Situ; Individual; Induction of Apoptosis; Infiltration; Invaded; Laws; Liquid substance; Mechanics; Mesenchymal; Microfluidic Microchips; Microfluidics; Modeling; Monitor; Operative Surgical Procedures; Patients; Pattern; Periodicity; Phenotype; Population; Proliferating; Proteins; Research; Role; Signal Transduction; Signal Transduction Pathway; Smooth Muscle Myocytes; Speed; Stenosis; Stimulus; Stress; Stretching; Structure; Students; Surface; System; Testing; Time; Tissue Engineering; Tissues; Traction; Transforming Growth Factor beta; Vascular Smooth Muscle; cardiac tissue engineering; cell behavior; cell motility; clinical translation; design; endothelial stem cell; experimental study; fluid flow; hands on research; heart valve replacement; hemodynamics; implantation; improved; in vivo; innovation; interstitial; migration; pediatric patients; precursor cell; reconstitution; recruit; repaired; response; scaffold; shear stress; skills; undergraduate student; valve replacement

Project Summary/Abstract We propose to determine how the hemodynamic environment regulates the attachment, invasion, and differentiation of host cells into “off-the-shelf” decellularized tissue engineered heart valves (TEHVs). We hypothesize that dynamic mechanical stretch and fluid shear stress regulate repopulation of the TEHV matrix by enhancing and aligning 3D matrix adhesions and activating latent TGF-beta from the matrix. To test our hypothesis, biopolymer scaffolds seeded with fibroblasts will be cast in stretchable wells and microfluidic chambers until remodeled into isotropic or aligned neo-tissues and then decellularized in situ. We will then quantify the extent to which vascular and circulating cells adhere to and invade the matrix under cyclic stretch (Aim 1) and dynamic flow conditions (Aim 2) relevant to in vivo implantation. Cell attachment, infiltration, proliferation, apoptosis, phenotype, and endothelial-to-mesenchymal transition markers will be quantitatively monitored over time. TGF-beta activation and 3D matrix adhesion protein content and alignment will be examined, and associated signal transduction pathways will be interrogated to determine the mechanisms governing the cell responses. The results from this systematic study will have a direct impact on TEHV development by determining the signals that aid (or hinder) host cell repopulation of the valve matrix with the goal of optimizing valve design for adaptive remodeling under complex in vivo conditions.

项目概要/摘要 我们建议确定血流动力学环境如何调节附着， 宿主细胞的侵袭和分化为“现成的”脱细胞组织工程 我们捕获了动态机械拉伸和流体剪切应力。 通过增强和对齐 3D 基质粘附来调节 TEHV 基质的重新填充 激活基质中潜在的 TGF-β 为了验证我们的假设，接种了生物聚合物支架。 含有成纤维细胞的细胞将被浇铸在可拉伸的孔和微流体室中，直到改造成 各向同性或对齐的新组织，然后原位脱细胞，然后我们将量化其程度。 血管和循环细胞在循环拉伸下粘附并侵入基质（目标 1）和与细胞附着相关的动态流动条件（目标2）。 浸润、增殖、凋亡、表型和内皮间质转化 随着时间的推移，将对 TGF-β 激活和 3D 基质粘附进行定量监测。 将检查蛋白质含量和排列，以及相关的信号转导途径 将被询问以确定控制细胞反应的机制。 这项系统研究将通过确定以下因素对 TEHV 的发展产生直接影响： 帮助（或阻碍）瓣膜基质的宿主细胞重新增殖的信号，目的是优化 复杂体内条件下自适应重塑的阀门设计。

项目成果

Reducing retraction in engineered tissues through design of sequential growth factor treatment.

通过连续生长因子治疗的设计减少工程组织的回缩。

• 发表时间: 2023-05-31
• 影响因子: 9
• 作者: Lei, Ying;Mungai, Rozanne;Li, Juanyong;Billiar, Kristen
• 通讯作者: Billiar, Kristen