Hydrogels for hMSC delivery & engraftment

项目总结 间充质干细胞(MSC)是一种具有广泛应用前景的再生医学细胞来源。 分离的MSC保持其自我更新能力，具有分化为多个谱系的潜力， 免疫原性低，可能是受损组织的家。在肌肉骨骼应用方面，移植了 在临床前模型和初步临床试验中，MSC增强了骨、软骨和椎间盘的修复。理学硕士 分泌大量细胞因子、生长因子和代谢物，调节免疫反应并促进 再生性活动。然而，移植的MSC成活率和植入率极低。 限制这些基于细胞的疗法。骨髓间充质干细胞存活、植入和功能的主要障碍是缺乏 合适的生物材料运送工具。在当前的资助期内，我们设计了特定于整合素的 合成水凝胶可调节间充质干细胞存活、植入、免疫调节分泌体和修复 在非愈合性骨缺损中的活动。由于使用的是人类细胞，这些研究仅限于 免疫缺陷小鼠。这项更新申请的目标是设计合成水凝胶，以促进 更相关的免疫活性模型中的MSC存活、免疫调节特性和骨修复。我们的 中心假说是整合素特异性水凝胶将支持MSC存活和免疫调节特性 指导宿主免疫细胞依赖的行动，以促进骨修复。这个项目的科学前提是 基于我们对工程整合素特定材料的令人信服的结果，该材料增强了移植的MSC 生存、功能和骨修复，以及利用有利于修复的单核细胞群体的策略。其基本原理是 因为这项研究将建立生物活性细胞输送载体，以提高MSC的存活率和 免疫调节和修复功能。目标1：设计促进MSC的合成水凝胶 免疫调节分泌体及其活性。目的2：评价工程水凝胶支持间充质干细胞的能力 增强骨骼的存活和免疫调节特性，以指导宿主免疫细胞依赖的作用 修理。这项拟议的研究具有很高的创新性，因为它专注于设计合成水凝胶来 控制MSC存活、免疫调节特性和骨修复。人源化老鼠的使用也是新奇的 并将提供关于基于hMSC的治疗的关键见解。这项研究预计将产生以下成果 重大成果。首先，我们将设计合成水凝胶来促进MSC的存活和 免疫调节、分泌和修复活性。第二，我们将确定MSC指导的程度 宿主免疫细胞参与骨修复。最后，这项研究将为MSC的存活率和 在免疫复杂性增加的模型中发挥作用。由于MSC的变革潜力，这 这项研究将对许多再生医学的应用具有广泛的意义和影响。

PROJECT SUMMARY Mesenchymal stem cells (MSC) represent a promising cell source for diverse regenerative medicine applications. Isolated MSC retain their self-renewal capacity, have the potential to differentiate into multiple lineages, are hypoimmunogenic, and can home to injured tissues. In the context of musculoskeletal applications, transplanted MSC enhance bone, cartilage, and intervertebral disc repair in pre-clinical models and initial clinical trials. MSC secrete a myriad of cytokines, growth factors and metabolites that modulate immune responses and promote regenerative activities. However, the extremely low survival and engraftment of transplanted MSC significantly limit these cell-based therapies. A major hurdle to MSC survival, engraftment, and function is the lack of appropriate biomaterial delivery vehicles. During the current funding period, we engineered integrin-specific synthetic hydrogels that modulate MSC survival, engraftment, immunomodulatory secretome, and reparative activities in non-healing bone defects. Because of the use of human cells, these studies were limited to immunodeficient mice. The objective of this renewal application is to engineer synthetic hydrogels that promote MSC survival, immunomodulatory properties, and bone repair in more relevant immunocompetent models. Our central hypothesis is that integrin-specific hydrogels will support MSC survival and immunomodulatory properties to direct host immune cell-dependent actions to enhance bone repair. The scientific premise for this project is based on our compelling results with engineered integrin-specific materials that enhance transplanted MSC survival, functions, and bone repair and strategies to harness pro-healing monocyte populations. The rationale for this research is that it will establish bioactive cell delivery vehicles that enhance MSC survival and immunomodulatory and reparative functions. Aim 1: Engineer synthetic hydrogels that promote MSC immunomodulatory secretome and activities. Aim 2: Evaluate the ability of engineered hydrogels to support MSC survival and immunomodulatory properties to direct host immune cell-dependent actions for enhanced bone repair. The proposed research is highly innovative because it focuses on engineering synthetic hydrogels to control MSC survival, immunomodulatory properties, and bone repair. The use of humanized mice is also novel and will provide critical insights on hMSC-based therapies. This research is expected to yield the following significant outcomes. First, we will engineer synthetic hydrogels that promote MSC survival and immunomodulatory secretory and reparative activities. Second, we will establish the extent to which MSC direct host immune cells in bone repair. Finally, this research will provide direct comparisons for MSC survival and function across models of increased immune complexity. Because of the transformative potential of MSC, this research will have broad significance and impact to many regenerative medicine applications.