Engineering Mesenchymal Stem Cell Microenvironments to Promote Immunomodulation

产品说明：炎性和免疫性疾病由于侵袭性炎症或炎症途径调节的缺陷而出现，并导致组织损伤和功能障碍。用于治疗这些疾病的药物治疗方案通常是无效的，这是由于复杂的发病机制和无法调节参与炎症反应和组织愈合的众多信号传导途径。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，这是由于它们能够调节复杂的炎症反应，主要是通过分泌各种细胞因子的旁分泌机制。MSC分泌的旁分泌因子不仅抑制促炎反应，而且促进内源性抗炎细胞表型，因此，具有调节多种信号通路和细胞类型的潜力，这些信号通路和细胞类型有助于炎症和免疫疾病的复杂发病机制。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的细胞数量不一致。MSC球状体的移植增加了细胞在移植部位的保留，可以提供一种改善基于MSC的炎症性疾病治疗的方法。此外，MSC的免疫调节可以受到细胞微环境的影响，例如炎性细胞因子的存在，因此操纵MSC微环境的物理和化学元素可以作为增强MSC分泌免疫调节旁分泌因子的新的和简单的手段。因此，该资助申请的主要目的是通过可移植3D干细胞微环境的工程化来调节人MSC（hMSC）免疫调节和旁分泌，以增强基于hMSC的疗法治疗炎性疾病的功效。本申请的中心假设是，在炎性肠病（IBD）的急性动物模型中，3D hMSC聚集体内细胞因子的呈递将增强旁分泌以抑制炎症反应并促进内源性抗炎表型。该应用是重要的，因为它检查了工程化3D MSC微环境的物理和生化元素的能力，以指导MSC旁分泌因子分泌并增强体内免疫调节能力。这种应用是创新的，因为这些结果将建立一种新的方法，用于工程MSC微环境，以在体内产生治疗相关的细胞群，可用于对抗各种不同的炎症和免疫疾病。

DESCRIPTION: 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 application 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 application 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 application 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 application 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.