Engineering Mesenchymal Stem Cell Microenvironments to Promote Immunomodulation

工程间充质干细胞微环境促进免疫调节

• 批准号: 9053165
• 负责人: Todd C McDevitt
• 金额: $ 21.36万
• 依托单位: J. DAVID GLADSTONE INSTITUTES
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-01 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9053165
• 关键词: Engineering; Mesenchymal; Stem; Cell; Microenvironments

PROJECT SUMMARY Inflammatory and immune diseases arise due to aggressive inflammation or defects in the regulation of inflammatory pathways and result in tissue damage and dysfunction. Drug treatment regimens used to treat these diseases are often ineffective due to the complex pathogenesis and the inability to regulate the numerous signaling pathways involved in inflammatory responses and tissue healing. Mesenchymal stem cells (MSCs) offer a potent cell therapy for the treatment of inflammatory and immune disorders due to their ability to regulate complex inflammatory responses, largely through paracrine mechanisms by secreting various cytokines. MSC secreted paracrine factors not only suppress pro-inflammatory responses but also promote endogenous anti-inflammatory cell phenotypes and therefore, have the potential to regulate the multiple signaling pathways and cell types that contribute to the complex pathogenesis of inflammatory and immune diseases. However, lack of a robust therapeutic response to MSCs is observed in disease models, in part due to inconsistent cell numbers at sites of inflammation. Transplantation of MSC spheroids, which increases retention of cells at transplant sites, may offer a means of improving MSC-based therapies for inflammatory diseases. Additionally, MSC immunomodulation can be influenced by the cellular microenvironment, such as the presence of inflammatory cytokines, therefore manipulating physical and chemical elements of the MSC microenvironment may serve as a novel and simple means of enhancing MSC secretion of immunomodulatory paracrine factors. Therefore, the primary objective of this grant proposal is to regulate human MSC (hMSC) immunomodulation and paracrine secretion through the engineering of transplantable 3D stem cell microenvironments to enhance the efficacy of hMSC-based therapies for the treatment of inflammatory diseases. The central hypothesis of this proposal is that presentation of cytokines within 3D hMSC aggregates will enhance paracrine secretion to suppress inflammatory responses and promote endogenous anti- inflammatory phenotypes in an acute animal model of inflammatory bowel disease (IBD). This proposal is significant because it examines the ability to engineer the physical and biochemical elements of 3D MSC microenvironments in order to direct MSC paracrine factor secretion and enhance immunomodulatory capability in vivo. This proposal is innovative because these results will establish a novel approach for engineering the MSC microenvironment to produce a therapeutically relevant cell population in vivo that can be used to combat a variety of different inflammatory and immune diseases.

项目摘要 炎性和免疫性疾病是由于侵袭性炎症或免疫调节缺陷引起的。 炎症途径并导致组织损伤和功能障碍。用于治疗的药物治疗方案 这些疾病由于复杂的发病机制和不能调节 参与炎症反应和组织愈合的众多信号通路。间充质干细胞 骨髓间充质干细胞（MSC）提供了一种有效的细胞疗法，用于治疗炎症和免疫疾病，因为它们能够 调节复杂的炎症反应，主要是通过旁分泌机制分泌各种 细胞因子MSC分泌的旁分泌因子不仅抑制促炎反应， 内源性抗炎细胞表型，因此，有可能调节多种 信号通路和细胞类型，有助于炎症和免疫的复杂发病机制， 疾病然而，在疾病模型中观察到缺乏对MSC的稳健治疗反应，部分原因是 炎症部位细胞数量不一致。MSC球状体的移植， 细胞保留在移植部位，可能提供一种改善基于MSC的炎症治疗的方法， 疾病此外，MSC免疫调节可受细胞微环境的影响，例如 炎性细胞因子的存在，因此操纵MSC的物理和化学元素 微环境可以作为一种新的和简单的手段，增强MSC分泌免疫调节物质， 旁分泌因子因此，本拨款提案的主要目标是监管人类MSC（hMSC） 通过可移植的3D干细胞工程实现免疫调节和旁分泌 微环境以增强基于hMSC的疗法治疗炎症性 疾病该建议的中心假设是细胞因子在3D hMSC聚集体中的呈递 将增强旁分泌，抑制炎症反应，促进内源性抗 在炎症性肠病（IBD）的急性动物模型中的炎性表型。这项建议是 重要的是，它检查了设计3D MSC的物理和生物化学元素的能力 微环境，以指导MSC旁分泌因子分泌和增强免疫调节功能。 在体内的能力。这项建议是创新的，因为这些结果将建立一个新的方法， 工程化MSC微环境以在体内产生治疗相关的细胞群， 用于对抗各种不同的炎症和免疫疾病。