Hydrogels for hMSC delivery & engraftment

项目摘要 间充质干细胞（MSC）代表了一种有前途的细胞来源，用于各种再生医学应用。 分离的MSC保留了它们的自我更新能力，具有分化成多个谱系的潜力， 低免疫原性的，并且可以归巢到损伤的组织。在肌肉骨骼应用的背景下， MSC在临床前模型和初始临床试验中增强骨、软骨和椎间盘修复。MSc 分泌无数细胞因子、生长因子和代谢物，调节免疫应答并促进 再生活动。然而，移植的MSC的极低存活率和植入显著降低， 限制了这些基于细胞的疗法。MSC存活、植入和功能的一个主要障碍是缺乏 合适的生物材料递送载体。在目前的资助期间，我们设计了整合素特异性 调节MSC存活、植入、免疫调节分泌组和修复的合成水凝胶 在非愈合性骨缺损中的活性。由于使用的是人体细胞，这些研究仅限于 免疫缺陷小鼠这项更新申请的目的是设计合成水凝胶， MSC存活、免疫调节特性和骨修复在更相关的免疫活性模型中的作用。我们 中心假设是整合素特异性水凝胶将支持MSC存活和免疫调节特性 引导宿主免疫细胞依赖性作用以增强骨修复。这个项目的科学前提是 基于我们令人信服的结果与工程整合素特异性材料，增强移植的MSC 存活、功能和骨修复以及利用促愈合单核细胞群的策略。的理由 这项研究的目的是建立生物活性细胞输送载体，提高MSC的存活率， 免疫调节和修复功能。目标1：设计促进MSC的合成水凝胶 免疫调节分泌组和活性。目的2：评价工程水凝胶支持MSC的能力 存活和免疫调节特性，以指导宿主免疫细胞依赖性作用，用于增强骨 修复.拟议的研究是高度创新的，因为它专注于工程合成水凝胶， 对照MSC存活、免疫调节特性和骨修复。人源化小鼠的使用也很新颖 并将为基于hMSC的治疗提供重要见解。这项研究预计将产生以下成果 重大成果。首先，我们将设计促进MSC存活的合成水凝胶， 免疫调节分泌和修复活性。其次，我们将确定MSC直接 宿主免疫细胞在骨修复中的作用最后，这项研究将提供MSC存活率的直接比较， 在增加免疫复杂性的模型中发挥作用。由于MSC的变革潜力， 研究将对许多再生医学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.