Hydrogels for hMSC delivery & engraftment

描述(申请人提供)：间充质干细胞(MSC)是再生医学应用的一种很有前途的细胞来源。在临床前模型和初步临床试验中，移植的MSC增强了骨、软骨和椎间盘的修复。然而，移植的MSC的植入率极低，其有益效果通常归因于营养/旁分泌作用。移植的MSC的低植入率和存活率显著限制了这些基于细胞的疗法在修复具有挑战性的、不可愈合的缺陷方面的作用。一个 骨髓间充质干细胞存活和植入的主要障碍是缺乏适当的生物活性载体。该项目的目标是设计生物功能水凝胶来指导人类间充质干细胞(HMSC)的存活、植入和功能。我们的中心假设是，呈现整合素特异性黏附配体的水凝胶将促进hMSC的植入、成骨和骨修复。这项工作将建立生物活性细胞输送载体，与现有的合成基质相比，提高MSC的存活、植入和功能。目的1：设计水凝胶，提出整合素特异的黏附配体，以指导hMSC的命运、承诺和分化。目的2：评价整合素特异性水凝胶促进人骨髓间充质干细胞存活、植入和骨修复的能力。目的：分析水凝胶共输送血管内皮生长因子对人骨髓间充质干细胞植入及骨修复的影响。这项研究具有创新性，因为它专注于利用整合素结合的特异性来控制hMSC的存活、植入和骨修复功能，并整合了新的体内成像方法。这项工作预计将产生以下成果。首先，我们将确定整合素特异性配体调节hMSC信号、承诺和分化为成骨、成脂和成软骨谱系的程度。我们还将建立新的生物活性细胞输送载体，以增强MSC的存活、植入和骨形成，以改善骨修复。最后，由于MSC的转化潜力，本研究将对许多再生医学的应用具有广泛的意义和影响。

DESCRIPTION (provided by applicant): Mesenchymal stem cells (MSC) represent a promising cell source for regenerative medicine applications. Transplanted MSC enhance bone, cartilage, and intervertebral disc repair in pre-clinical models and initial clinical trials. Howevr, the engraftment of transplanted MSC is extremely low, and the beneficial effects are generally attributed to trophic/paracrine actions. The low engraftment and survival of transplanted MSC significantly limit these cell-based therapies in the repair of challenging, non-healing defects. A major hurdle to MSC survival and engraftment is the lack of appropriate bioactive delivery vehicles. The objective of this project is to engineer biofunctional hydrogels to direct human MSC (hMSC) survival, engraftment, and function. Our central hypothesis is that hydrogels presenting integrin-specific adhesive ligands will promote hMSC engraftment, osteogenesis, and bone repair. This work will establish bioactive cell delivery vehicles that enhance MSC survival, engraftment and function compared to existing synthetic matrices. Aim 1: Engineer hydrogels presenting integrin-specific adhesive ligands to direct hMSC fate commitment and differentiation. Aim 2: Evaluate the ability of integrin-specific hydrogels to promote hMSC survival, engraftment, and bone repair. Aim 3: Analyze the effects of VEGF co-delivery from hydrogels on hMSC engraftment and bone repair. The proposed research is innovative because it focuses on exploiting integrin binding specificity to control hMSC survival, engraftment and function for bone repair and integrates new in vivo imaging approaches. This work is expected to yield the following outcomes. First, we will determine the extent to which integrin-specific ligands regulate hMSC signaling, commitment and differentiation into osteogenic, adipogenic and chondrogenic lineages. We will also establish novel bioactive cell delivery vehicles that enhance MSC survival, engraftment and bone formation for improved bone repair. Finally, because of the transformative potential of MSC, this research will have broad significance and impact to many regenerative medicine applications.