Papalamprou Angela, Chang Chia Wei, Vapniarsky Natalia, Clark Alycia, Walker Naomi, Griffiths Leigh G
Molecular Cellular and Integrative Physiology Graduate Group, University of California, Davis, CA, United States; Department of Medicine and Epidemiology, School of Veterinary Medicine, University of California, Davis, CA, United States.
Department of Medicine and Epidemiology, School of Veterinary Medicine, University of California, Davis, CA, United States.
Acta Biomater. 2016 Nov;45:155-168. doi: 10.1016/j.actbio.2016.07.032. Epub 2016 Jul 18.
Cardiac extracellular matrix (cECM) scaffolds are promising biomaterials for reconstructive surgery applications since they possess the structure/function properties of native tissue. Production of cECM scaffolds has been achieved using decellularization approaches, which commonly employ denaturing detergents, such as sodium dodecyl sulfate (SDS). Our antigen removal (AR) method has been shown to remove cellular and nonmyocyte components, while preserving cECM scaffold structure/function relationships. Here, we demonstrate that more human mesenchymal stem cells (MSCs) invaded AR scaffolds compared to SDS controls. Additionally, AR scaffolds stimulated a constructive remodeling response similar to allograft controls, and were transformed to adipose tissue in a xenogeneic rat to mouse subpannicular in vivo model. Conversely, SDS scaffolds showed a chronic inflammatory response that worsened throughout the 12-wk time course preventing constructive remodeling and mirroring the response seen towards xenogeneic tissue. AR scaffolds and xenogeneic controls recellularized with murine MSCs (mMSCs) were also implanted to assess whether mMSCs would offer any additive benefit in overcoming residual scaffold-specific immune responses. Paradoxically, recellularization resulted in chronic inflammatory response in AR-recellularized scaffolds. We conclude that AR cECM scaffolds represent a promising biomaterial, which is accepted by the recipient as self in origin and fosters implantation site appropriate regenerative responses.
We demonstrated that an antigen-removal (AR) approach utilizing principles of differential solubility for production of a xenogeneic rat cardiac extracellular matrix scaffold results in improved recellularization efficiency with human and mouse mesenchymal stem cells (MSCs) in vitro. Furthermore, we tested the immune response to AR scaffolds versus allograft and xenograft controls with or without MSC recellularization using a rat to mouse subcutaneous model. We showed that AR scaffolds and allograft controls resulted in significant adipose tissue transformation after 12weeks. Paradoxically, MSCs had a positive impact in the immune response to xenografts, but had the opposite effect in AR scaffolds, resulting in chronic inflammatory response, which might be attributed to a change of their phenotype following recellularization into scaffolds.
心脏细胞外基质（cECM）支架是用于重建手术的有前景的生物材料，因为它们具有天然组织的结构/功能特性。使用去细胞方法已实现cECM支架的生产，该方法通常使用变性去污剂，如十二烷基硫酸钠（SDS）。我们的抗原去除（AR）方法已被证明可去除细胞和非心肌细胞成分，同时保留cECM支架的结构/功能关系。在此，我们证明与SDS对照组相比，更多的人间充质干细胞（MSC）侵入AR支架。此外，AR支架刺激了类似于同种异体移植对照组的建设性重塑反应，并在异种大鼠到小鼠皮下体内模型中转化为脂肪组织。相反，SDS支架显示出慢性炎症反应，在整个12周的时间过程中恶化，阻止了建设性重塑，并反映了对异种组织的反应。用小鼠MSC（mMSC）重新细胞化的AR支架和异种对照也被植入，以评估mMSC是否会在克服残留的支架特异性免疫反应方面提供任何额外的益处。矛盾的是，重新细胞化导致AR重新细胞化支架中的慢性炎症反应。我们得出结论，AR cECM支架代表一种有前景的生物材料，其被受体视为自身来源并促进植入部位适当的再生反应。
我们证明，利用差异溶解度原理生产异种大鼠心脏细胞外基质支架的抗原去除（AR）方法可提高体外人源和小鼠间充质干细胞（MSC）的重新细胞化效率。此外，我们使用大鼠到小鼠皮下模型测试了对AR支架与同种异体移植和异种移植对照（有无MSC重新细胞化）的免疫反应。我们表明，AR支架和同种异体移植对照在12周后导致显著的脂肪组织转化。矛盾的是，MSC对异种移植的免疫反应有积极影响，但在AR支架中有相反的效果，导致慢性炎症反应，这可能归因于它们重新细胞化进入支架后表型的改变。
