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 间充质干细胞/基质细胞（MSC）是免疫细胞的有效调节剂，其免疫抑制作用 正在积极研究其功能以用于许多治疗应用。特别是，它已经 证明MSCs可以抑制效应T细胞的增殖并诱导调节性T细胞 分化治疗移植物抗宿主病（GvHD）。部分MSC产品已获批准 美国以外国家的监管机构 然而，MSC 并不总是表现出一致的 GvHD 临床试验中的疗效。这部分是由于生成具有一致、高水平的 MSC 所面临的挑战。 治疗效力。该项目的总体目标是开发具有增强功能的 MSC 疗法 通过识别和提供最佳微环境来提高 GvHD 治疗的免疫抑制功效 MSC 生产中的机械线索。来自细胞微环境的机械信号在 调节细胞行为。例如，研究表明基质硬度指导细胞活动和命运 例如迁移、增殖和分化。然而，基体或材料刚度仅描述它们的 静态、弹性机械性能。天然的细胞外基质 (ECM) 和活体不是简单的弹性物质 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（应力松弛在 不同的费率）。我们开发了一种水凝胶系统，可以概括刚度和粘弹性 不同类型组织的行为。使用水凝胶作为培养基质，我们发现基质 除刚度外，应力松弛也是调节细胞与 ECM 相互作用的重要机械因素 指导 MSC 活动，包括扩散、增殖、分化和体内骨再生。在 我们与 FDA 的 Kyung Sung 博士合作，最近发现基质应力松弛也调节 MSC的免疫抑制能力及其抑制T细胞增殖的能力；有趣的是，间充质干细胞保留 即使从水凝胶中提取后，它们的机械“记忆”仍然存在（参见初步数据部分）。在 根据这些新发现，我们假设具有定制应力松弛特性的生物材料可以 在 MSC 生产中提供诱导机械线索，以增强 MSC 的免疫抑制功效 GvHD 治疗。我们将在以下具体目标中检验这一假设： 目标 1：阐明分子 基质应力松弛调节人间充质干细胞免疫抑制能力的机制 (hMSC) 源自骨髓。目标 2：比较基质应力松弛对衍生的 hMSC 的影响 来自不同组织或 hMSC 亚群，按整合素表达进行分类。目标 3：评估效果 由具有不同应力松弛特性的粘弹性水凝胶引发的 hMSC，用于 GvHD 治疗 动物模型。该项目采用多学科方法来研究 hMSC 机械生物学。成功的 完成这些目标将对理解矩阵机械线索如何调节产生重大影响 hMSC 的免疫抑制能力，这些发现可能会导致更好的 GvHD 治疗。