Efficient cell delivery strategies are urgently needed to improve the outcome of cell-based pro-angiogenic therapies. This study describes the design of an injectable cell delivery platform, based on biomaterial-guided morphogenesis principles. Soft high-mannuronic acid alginate microgels, oxidized and functionalized with integrin-binding peptides, provided adequate biochemical/biomechanical cues for the co-assembly of mesenchymal stem cells and outgrowth endothelial cells (OEC) into pre-vascularized microtissues. In vitro priming conditions regulated OEC tubulogenesis, which only occurred under normoxia (+O₂) in the presence of angiogenic factors (+GF) and, importantly, did not revert in an ischemic-like environment. Primed (+O₂+GF) microgel-entrapped cells secreted a large variety of angiogenesis-related proteins and produced endogenous extracellular-matrix, rich in fibronectin and collagen type IV, fostering cell-cell/cell-matrix interactions and establishing a stable angiogenic niche. Extending the pre-culture time resulted in higher cell outward migration and in vivo angiogenic potential. Microgels partially disintegrated upon implantation in chick embryos, promoting interaction between pre-vascularized microtissues and the host. Preserved human vascular structures were still detected in vivo, and human cells showed the ability to migrate and integrate with the chick vasculature. Our results suggest that an integrated approach combining pro-angiogenic cells, cell-instructive microgels and adequate in vitro priming may provide the basis for successful therapeutic angiogenesis.

中文翻译：

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指导细胞指导性微凝胶的形态发生用于治疗性血管生成

迫切需要有效的细胞递送策略来改善基于细胞的促血管生成疗法的疗效。这项研究描述了基于生物材料指导的形态发生原理的可注射细胞递送平台的设计。软的高甘露糖醛酸海藻酸盐微凝胶，经整联蛋白结合肽氧化并功能化，为间充质干细胞和内皮细胞（OEC）共同组装成血管形成前的微组织提供了足够的生化/生物力学提示。体外启动条件调节OEC肾小管生成，仅在常氧（+ O ₂）下存在血管生成因子（+ GF）的情况下发生，重要的是，在缺血性环境中没有恢复。灌注（+ O ₂+ GF）包裹的微凝胶细胞分泌大量与血管生成相关的蛋白质，并产生内源性细胞外基质，富含纤连蛋白和IV型胶原，促进细胞-细胞/细胞-基质相互作用并建立稳定的血管生成位。延长预培养时间会导致更高的细胞向外迁移和体内血管生成潜能。植入鸡胚后，微凝胶会部分崩解，从而促进血管形成前的微组织与宿主之间的相互作用。体内仍然可以检测到保存的人血管结构，人细胞具有迁移和整合雏鸡脉管系统的能力。我们的结果表明，将促血管生成细胞，细胞指导性微凝胶和适当的血管生成结合起来的综合方法体外灌注可能为成功的治疗性血管生成提供基础。