Petrosyan Astgik, Da Sacco Stefano, Tripuraneni Nikita, Kreuser Ursula, Lavarreda-Pearce Maria, Tamburrini Riccardo, De Filippo Roger E, Orlando Giuseppe, Cravedi Paolo, Perin Laura
GOFARR Laboratory for Organ Regenerative Research and Cell Therapeutics, Saban Research Institute, Children's Hospital Los Angeles, Department of Urology, University of Southern California, Los Angeles, CA 90027, USA.
Radboud Institute for Molecular Life Sciences, Department of Physiology, 6525 GA Nijmegen, The Netherlands.
Matrix Biol. 2017 Jan;57-58:334-346. doi: 10.1016/j.matbio.2016.08.009. Epub 2016 Aug 26.
The outcome of tissue engineered organ transplants depends on the capacity of the biomaterial to promote a pro-healing response once implanted in vivo. Multiple studies, including ours, have demonstrated the possibility of using the extracellular matrix (ECM) of animal organs as platform for tissue engineering and more recently, discarded human organs have also been proposed as scaffold source. In contrast to artificial biomaterials, natural ECM has the advantage of undergoing continuous remodeling which allows adaptation to diverse conditions. It is known that natural matrices present diverse immune properties when compared to artificial biomaterials. However, how these properties compare between diseased and healthy ECM and artificial scaffolds has not yet been defined. To answer this question, we used decellularized renal ECM derived from WT mice and from mice affected by Alport Syndrome at different time-points of disease progression as a model of renal failure with extensive fibrosis. We characterized the morphology and composition of these ECMs and compared their in vitro effects on macrophage activation with that of synthetic scaffolds commonly used in the clinic (collagen type I and poly-L-(lactic) acid, PLLA). We showed that ECM derived from Alport kidneys differed in fibrous protein deposition and cytokine content when compared to ECM derived from WT kidneys. Yet, both WT and Alport renal ECM induced macrophage differentiation mainly towards a reparative (M2) phenotype, while artificial biomaterials towards an inflammatory (M1) phenotype. Anti-inflammatory properties of natural ECMs were lost when homogenized, hence three-dimensional structure of ECM seems crucial for generating an anti-inflammatory response. Together, these data support the notion that natural ECM, even if derived from diseased kidneys promote a M2 protolerogenic macrophage polarization, thus providing novel insights on the applicability of ECM obtained from discarded organs as ideal scaffold for tissue engineering.
组织工程化器官移植的结果取决于生物材料在植入体内后促进愈合反应的能力。包括我们的研究在内的多项研究已经证明，利用动物器官的细胞外基质（ECM）作为组织工程平台是可行的，并且最近也有人提出将废弃的人体器官作为支架来源。与人工生物材料相比，天然ECM具有持续重塑的优势，这使其能够适应各种条件。众所周知，与人工生物材料相比，天然基质具有不同的免疫特性。然而，患病和健康的ECM与人工支架之间的这些特性如何比较尚未明确。为了回答这个问题，我们使用了来自野生型小鼠以及在疾病进展不同时间点受阿尔波特综合征影响的小鼠的脱细胞肾ECM，作为具有广泛纤维化的肾衰竭模型。我们对这些ECM的形态和组成进行了表征，并将它们在体外对巨噬细胞激活的影响与临床常用的合成支架（I型胶原蛋白和聚-L-乳酸，PLLA）进行了比较。我们发现，与来自野生型肾脏的ECM相比，来自阿尔波特肾脏的ECM在纤维蛋白沉积和细胞因子含量方面存在差异。然而，野生型和阿尔波特肾ECM都主要诱导巨噬细胞向修复性（M2）表型分化，而人工生物材料则诱导其向炎症性（M1）表型分化。天然ECM的抗炎特性在匀浆后丧失，因此ECM的三维结构似乎对产生抗炎反应至关重要。总之，这些数据支持这样一种观点，即天然ECM，即使来自患病肾脏，也能促进M2促耐受性巨噬细胞极化，从而为将废弃器官获得的ECM作为组织工程理想支架的适用性提供了新的见解。
