Engineering Mesenchymal Stromal Cells to treat Muscle Fibrosis

工程间充质基质细胞治疗肌肉纤维化

基本信息

批准号：
10904157
负责人：
Sing-Wan Wong
金额：
$ 24.9万
依托单位：
COLORADO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-01 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10904157
关键词：
Advisory Committees Affect Alginates Biochemical Biocompatible Materials Biodistribution Biomedical Engineering Biophysics Bone Marrow Cell Therapy Cell Volumes Cells Chemicals Cicatrix Clinical Clinical Trials Collagen Committee Members Cues Data Deposition Diffusion Disease Disease Progression Encapsulated Engineering Ensure Environment Extracellular Matrix Fibrosis Functional disorder Gastrocnemius Muscle Gel Goals Hydrogels Image Impairment Individual Inflammatory Injectable Injections Integrins Interstitial Collagenase Ischemia Kinetics Knowledge Laboratories Ligands Marrow Mechanics Mediating Methods Microfluidics Modeling Molecular Mus Muscle Muscle function Muscular Atrophy Muscular Dystrophies Myopathy NF-kappa B Organ Oxidative Stress Induction Patients Phase Process Production Property Publishing RGD (sequence)RNA Interference RNA delivery Recombinants Regenerative Medicine Reperfusion Therapy Research Personnel Research Project Grants Role Signal Transduction Skeletal Muscle Skeletal bone Specific qualifier value TNF gene TNFRSF1A gene Technology Testing Therapeutic Thick Thinness Tissues Tumor Necrosis Factor Receptor Work animal imaging biophysical techniques career development collagenase 3 confocal imaging cytokine design dysadherin effective therapy experience functional restoration immunoregulation improved in vivo mdx mouse mechanical signal member mesenchymal stromal cell meter miniaturize muscle regeneration muscle strength muscular dystrophy mouse model novel novel therapeutic intervention paracrine prevent programs public health relevance response stem cells success tissue regeneration viscoelasticity

项目摘要

Project Summary Mesenchymal stromal cells (MSCs) have been tested in nearly one thousand clinical trials, mostly because of their ability to secrete factors that can modify host environments. For instance, MSCs can adapt to their niches and remodel the extracellular matrix. While this property of MSCs can potentially be beneficial to treat fibrosis and promote tissue regeneration, leveraging this property has been challenging because specific signals that enable MSCs to remodel the matrix remain to be defined and leveraged in MSC-based therapeutics. Here, we describe a highly efficient approach to encapsulate individual cells in engineered gel coatings with specifically defined biophysical and biochemical cues. We have developed this approach to show that soft, thin gel coating is an enabling cue that increases the production of soluble interstitial collagenases in response to tumor necrosis factor-α (TNFα). Importantly, our preliminary data show that gel-coated MSCs decrease collagen deposition in a murine muscular dystrophy model. In this K99/R00 proposal, I will build upon these results to test the hypothesis that programming of MSCs using specifically engineered microgels activates the potential of MSCs to inhibit muscle fibrosis. In Aim 1, we will determine the role of engineered gel coating in TNFα- induced activation of MSCs to produce high levels of interstitial collagenases and degrade collagen, and understand mechanisms behind this process. In Aim 2, we will investigate the role of gel-coated MSCs in inhibiting muscle fibrosis and restoring muscle functions. Success of this proposal will lead to an effective strategy to treat muscle fibrosis, which is a major unmet clinical need. During the K99 phase, I will work with my advisory committee to enhance my knowledge in biomaterial design, cellular mechanobiology, pathophysiology of fibrosis, as well as advanced microtechnologies, imaging, and computational approaches to effectively drive this research project. These experiences together with career development activities described in this proposal will ensure my smooth transition to an independent investigator at the interface between mechanobiology and bioengineering to develop novel therapeutic strategies for muscle disorders.

项目概要间充质基质细胞（MSC）已在近千项临床试验中进行了测试，主要是因为它们具有分泌可以改变宿主环境的因子的能力，例如，间充质干细胞可以适应它们的生态位。并重塑细胞外基质，而间充质干细胞的这种特性可能有利于治疗纤维化。并促进组织再生，利用这一特性一直具有挑战性，因为特定的信号使 MSC 能够重塑基质仍有待定义并在基于 MSC 的治疗中得到利用。描述了一种高效的方法，将单个细胞封装在工程凝胶涂层中，特别是我们开发了这种方法来显示柔软、薄的凝胶涂层。是一种促进信号，可增加可溶性间质胶原酶的产生以响应肿瘤重要的是，我们的初步数据表明，凝胶涂层的 MSC 会减少胶原蛋白。在此 K99/R00 提案中，我将基于这些结果来检验以下假设：使用专门设计的微凝胶对 MSC 进行编程可激活潜力 MSC 抑制肌肉纤维化在目标 1 中，我们将确定工程凝胶涂层在 TNFα- 中的作用。诱导 MSC 活化，产生高水平的间质胶原酶并降解胶原蛋白，以及在目标 2 中，我们将了解凝胶涂层 MSC 在这一过程中的作用。抑制肌肉纤维化和恢复肌肉功能这一建议的成功将带来有效的结果。治疗肌肉纤维化的策略，这是一个主要的未满足的临床需求，在 K99 阶段，我将致力于研究。我的咨询委员会旨在增强我在生物材料设计、细胞力学生物学、纤维化的病理生理学，以及先进的微技术、成像和计算方法这些经验与所描述的职业发展活动一起有效地推动了该研究项目。在本提案中，将确保我顺利过渡为独立调查员机械生物学和生物工程开发肌肉疾病的新治疗策略。