Mechanical programming to enhance the immunosuppressive function of mesenchymal stem cells for the treatment of graft-versus-host disease.

机械编程增强间充质干细胞的免疫抑制功能，用于治疗移植物抗宿主病。

• 批准号: 10905160
• 负责人: Luo Gu
• 金额: $ 39.4万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-07 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10905160
• 关键词: Actomyosin; Acute Graft Versus Host Disease; Adipose tissue; Affect; Allogenic; Animal Model; Animals; Behavior; Biochemical; Biocompatible Materials; Biological Response Modifiers; Blood; Body Weight decreased; Bone Marrow; Bone Regeneration; Canada; Cell Therapy; Cell secretion; Cells; Characteristics; Chronic; Clinical Trials; Collaborations; Country; Data; Dinoprostone; Elasticity; Elements; Exhibits; Extracellular Matrix; Galactose Binding Lectin; Goals; Hematopoietic Stem Cell Transplantation; Histopathology; Human; Hydrogels; Immunosuppression; Integrin Binding; Integrins; Japan; Light; Mechanics; Mediating; Memory; Mesenchymal; Mesenchymal Stem Cells; Molecular; Monitor; Morbidity - disease rate; New Zealand; Nuclear Lamin; Nuclear Translocation; Play; Posture; Production; Proliferating; Property; Prophylactic treatment; Regulatory T-Lymphocyte; Relaxation; Research; Role; Serum; Signaling Molecule; Sorting; Stress; Stromal Cells; Surface; System; T cell differentiation; T-Cell Proliferation; T-Lymphocyte; Testing; Therapeutic; Time; Tissues; Transforming Growth Factor beta; Transplant Recipients; Treatment Efficacy; Umbilical cord structure; cell behavior; cytokine; effector T cell; efficacy evaluation; graft vs host disease; humanized mouse; in vivo; interdisciplinary approach; manufacture; mechanical properties; mechanical signal; mechanotransduction; migration; mortality; mouse model; programmed cell death ligand 1; response; rho GTP-Binding Proteins; stem; treatment strategy; viscoelasticity

SPECIFIC AIMS Mesenchymal stem/stromal cells (MSCs) are potent regulators of immune cells, and their immunosuppressive function is being actively investigated for a number of therapeutic applications. In particular, it has been demonstrated that MSCs can inhibit the proliferation of effector T cells and induce regulatory T-cell differentiation for treating graft versus host disease (GvHD). A few MSC products have been approved by regulatory agencies in countries outside of the U.S. However, MSCs have not always shown consistent efficacy in GvHD clinical trials. This is in part due to the challenges of generating MSCs with consistent, high therapeutic potency. The overarching goal of this project is to develop MSC therapies with enhanced immunosuppressive efficacy for GvHD treatment by identifying and providing optimal microenvironment mechanical cues in MSC production. Mechanical cues from cell microenvironment play important roles in regulating cell behavior. For example, studies have shown that matrix stiffness directs cell activity and fate such as migration, proliferation, and differentiation. However, matrix or material stiffness only describes their static, elastic mechanical property. Instead of being simply elastic, natural extracellular matrix (ECM) and living tissues are viscoelastic, exhibiting stress relaxation over different characteristic time scales (stress relaxes at different rates). We have developed a hydrogel system that can recapitulate the stiffness and viscoelastic behavior of different types of tissues. Using the hydrogels as culture substrates, we discovered that matrix stress relaxation, in addition to stiffness, is an important mechanical factor regulating cell–ECM interactions and directing MSC activities including spreading, proliferation, differentiation, and in vivo bone regeneration. In collaboration with Dr. Kyung Sung at FDA, we recently found that substrate stress relaxation also regulates MSC's immunosuppressive capacity and their ability to inhibit T cell proliferation; Interestingly, MSCs retained their mechanical “memory” even after being extracted from the hydrogels (see preliminary data section). In light of these new findings, we hypothesize that biomaterials with tailored stress relaxation properties can provide inducing mechanical cues in MSC production to enhance MSC's immunosuppressive efficacy for GvHD treatment. We will test this hypothesis in the following specific aims: Aim 1: Elucidate the molecular mechanisms by which matrix stress relaxation regulates the immunosuppressive capacity of human MSCs (hMSC) derived from bone marrow. Aim 2: Compare the effect of matrix stress relaxation on hMSCs derived from different tissues or hMSC subpopulations sorted by integrin expression. Aim 3: Evaluate the efficacy of hMSCs primed by viscoelastic hydrogels with different stress relaxation properties for GvHD treatment in an animal model. This project uses multidisciplinary approaches to study hMSC mechanobiology. Successful completion of these aims will have significant impact in understanding how matrix mechanical cues regulates the immunosuppressive capacity of hMSCs, with the findings potentially leading to better treatment for GvHD.

具体目标 间充质茎/基质细胞（MSC）是免疫抑制的潜在调节剂 正在积极研究许多治疗应用。特别是 证明MSC可以抑制效应T细胞的增殖并诱导调节性T细胞 治疗移植物与宿主疾病（GVHD）的分化。一些MSC产品已由 但是，美国以外国家的监管机构并不总是显示一致 GVHD临床试验的功效。这部分是由于生成一致，高的MSC的挑战 治疗效力。该项目的总体目标是开发具有增强的MSC疗法 通过识别和提供最佳微环境，用于GVHD处理的免疫抑制效率 MSC生产中的机械提示。细胞微环境的机械提示在 调节细胞行为。例如，研究表明矩阵刚度指导细胞活性和命运 例如迁移，增殖和分化。但是，矩阵或材料刚度仅描述 静态机械性能。而不是简单地弹性，天然的细胞外基质（ECM）和生活 组织是粘弹性的，在不同的特征时间尺度上表现出应力松弛（应力在 不同的价格）。我们已经开发了一个水凝胶系统，该系统可以概括刚度和粘弹性 不同类型的组织的行为。使用水凝胶作为培养基底物，我们发现了矩阵 除刚度外，压力松弛是调节细胞 - ECM相互作用的重要机械因子 并指导MSC活动，包括扩散，扩散，分化和体内骨再生。在 与FDA的Kyung Sung博士合作，我们最近发现底物应力放松也可以调节 MSC的免疫抑制能力及其抑制T细胞增殖的能力；有趣的是，保留了MSC 即使从水凝胶中提取后，它们的机械“记忆”（请参阅​​初步数据部分）。在 这些新发现的灯光，我们假设具有定制应力放松特性的生物材料可以 在MSC生产中提供诱导机械提示，以提高MSC的免疫抑制效率 GVHD处理。我们将在以下特定目的中检验该假设：目标1：阐明分子 基质应力松弛调节人MSC的免疫抑制能力的机制 （HMSC）源自骨髓。目标2：比较基质应力放松对衍生的HMSC的影响 来自不同组织或HMSC亚群，通过整联蛋白表达排序。目标3：评估效率 HMSC由具有不同应力松弛特性的粘弹性水凝胶引发，用于GVHD处理 动物模型。该项目使用多学科方法来研究HMSC机械生物学。成功的 这些目标的完成将对理解矩阵机械提示如何调节产生重大影响 HMSC的免疫抑制能力，发现可能导致更好的GVHD治疗。