人类白细胞抗原
移植
基因沉默
基因敲除
血栓调节蛋白
癌症研究
免疫学
生物
细胞生物学
医学
细胞培养
抗原
凝血酶
内科学
遗传学
基因
血小板
生物化学
作者
Bettina Wiegmann,Constança Figueiredo,C Gras,Michael Pflaum,Sabrina Schmeckebier,Sotirios Korossis,Axel Haverich,Rainer Blasczyk
出处
期刊:Biomaterials
[Elsevier]
日期:2014-09-01
卷期号:35 (28): 8123-8133
被引量:35
标识
DOI:10.1016/j.biomaterials.2014.06.007
摘要
Variability in Human Leukocyte Antigens (HLA) remains a hurdle to the application of allogeneic cellular products. Due to insufficient autologous endothelial cell harvesting for the biohybrid lung, allogeneic human cord blood derived endothelial cells (HCBEC) were used for the endothelialization of poly-4-methyl-1-pentene (PMP) gas exchange membranes. Therefore, HLA class I expression was silenced stably in HCBECs to prevent rejection. The capacity of HLA class I-silenced HCBEC to abrogate allogeneic immune responses, their functional properties and suitability for endothelialization of PMP membranes were investigated. Delivery of β2-microglobulin (β2m)-specific shRNAs reduced β2m mRNA levels by up to 90% and caused a knockdown of HLA class I expression by up to 85%. HLA-silenced HCBEC abrogated T-cell responses and escaped antibody-mediated complement-dependent cytotoxicity. The EC phenotype and cytokine secretion profiles between HLA-expressing or -silenced HCBEC remained unaltered. EC specific activation (e.g. ICAM) and thrombogenic markers (e.g. thrombomodulin) remained unaffected by HLA-silencing, but their expression was upregulated by TNFα-stimulation. Furthermore, HLA-silenced HCBECs showed high proliferation rates and built an EC monolayer onto PMP membranes. This study represents a new therapeutic concept in the field of cell and organ transplantation and may bring the bioartificial lung as an alternative to lung transplantation closer to reality.
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