Fonseca Keila B, Gomes David B, Lee Kangwon, Santos Susana G, Sousa Aureliana, Silva Eduardo A, Mooney David J, Granja Pedro L, Barrias Cristina C
INEB - Instituto de Engenharia Biomédica, Universidade do Porto , Rua do Campo Alegre 823, 4150-180 Porto, Portugal.
Biomacromolecules. 2014 Jan 13;15(1):380-90. doi: 10.1021/bm4016495. Epub 2013 Dec 18.
Hydrogels with the potential to provide minimally invasive cell delivery represent a powerful tool for tissue-regeneration therapies. In this context, entrapped cells should be able to escape the matrix becoming more available to actively participate in the healing process. Here, we analyzed the performance of proteolytically degradable alginate hydrogels as vehicles for human mesenchymal stem cells (hMSC) transplantation. Alginate was modified with the matrix metalloproteinase (MMP)-sensitive peptide Pro-Val-Gly-Leu-Iso-Gly (PVGLIG), which did not promote dendritic cell maturation in vitro, neither free nor conjugated to alginate chains, indicating low immunogenicity. hMSC were entrapped within MMP-sensitive and MMP-insensitive alginate hydrogels, both containing cell-adhesion RGD peptides. Softer (2 wt % alginate) and stiffer (4 wt % alginate) matrices were tested. When embedded in a Matrigel layer, hMSC-laden MMP-sensitive alginate hydrogels promoted more extensive outward cell migration and invasion into the tissue mimic. In vivo, after 4 weeks of subcutaneous implantation in a xenograft mouse model, hMSC-laden MMP-sensitive alginate hydrogels showed higher degradation and host tissue invasion than their MMP-insensitive equivalents. In both cases, softer matrices degraded faster than stiffer ones. The transplanted hMSC were able to produce their own collagenous extracellular matrix, and were located not only inside the hydrogels, but also outside, integrated in the host tissue. In summary, injectable MMP-sensitive alginate hydrogels can act as localized depots of cells and confer protection to transplanted cells while facilitating tissue regeneration.
具有微创细胞递送潜力的水凝胶是组织再生疗法的有力工具。在这种情况下，包封的细胞应能够从基质中逸出，更易于积极参与愈合过程。在此，我们分析了可蛋白水解降解的藻酸盐水凝胶作为人间充质干细胞（hMSC）移植载体的性能。藻酸盐用基质金属蛋白酶（MMP）敏感肽Pro-Val-Gly-Leu-Iso-Gly（PVGLIG）修饰，该肽在体外不促进树突状细胞成熟，无论是游离的还是与藻酸盐链缀合的，表明免疫原性低。hMSC被包封在MMP敏感和MMP不敏感的藻酸盐水凝胶中，两者都含有细胞粘附RGD肽。测试了较软（2 wt%藻酸盐）和较硬（4 wt%藻酸盐）的基质。当嵌入基质胶层中时，负载hMSC的MMP敏感藻酸盐水凝胶促进了更广泛的向外细胞迁移和向组织模拟物中的侵袭。在体内，在异种移植小鼠模型中皮下植入4周后，负载hMSC的MMP敏感藻酸盐水凝胶比其MMP不敏感的同类物显示出更高的降解和宿主组织侵袭。在这两种情况下，较软的基质比较硬的基质降解得更快。移植的hMSC能够产生自己的胶原细胞外基质，并且不仅位于水凝胶内部，还位于外部，整合到宿主组织中。总之，可注射的MMP敏感藻酸盐水凝胶可以作为细胞的局部储存库，为移植的细胞提供保护，同时促进组织再生。
