Ruiz-Rosado Juan de Dios, Lee Yong-Ung, Mahler Nathan, Yi Tai, Robledo-Avila Frank, Martinez-Saucedo Diana, Lee Avione Y, Shoji Toshihiro, Heuer Eric, Yates Andrew R, Pober Jordan S, Shinoka Toshiharu, Partida-Sanchez Santiago, Breuer Christopher K
Tissue Engineering Center, Nationwide Children's Hospital, Columbus, Ohio, USA.
Center for Microbial Pathogenesis, Nationwide Children's Hospital, Columbus, Ohio, USA.
FASEB J. 2018 Jun 15;32(12):fj201800458. doi: 10.1096/fj.201800458.
We previously developed a tissue-engineered vascular graft (TEVG) made by seeding autologous cells onto a biodegradable tubular scaffold, in an attempt to create a living vascular graft with growth potential for use in children undergoing congenital heart surgery. Results of our clinical trial showed that the TEVG possesses growth capacity but that its widespread clinical use is not yet advisable due to the high incidence of TEVG stenosis. In animal models, TEVG stenosis is caused by increased monocytic cell recruitment and its classic ("M1") activation. Here, we report on the source and regulation of these monocytes. TEVGs were implanted in wild-type, CCR2 knockout ( Ccr2), splenectomized, and spleen graft recipient mice. We found that bone marrow-derived Ly6C monocytes released from sequestration by the spleen are the source of mononuclear cells infiltrating the TEVG during the acute phase of neovessel formation. Furthermore, short-term administration of losartan (0.6 g/L, 2 wk), an angiotensin II type 1 receptor antagonist, significantly reduced the macrophage populations (Ly6C/F480) in the scaffolds and improved long-term patency in TEVGs. Notably, the combined effect of bone marrow-derived mononuclear cell seeding with short-term losartan treatment completely prevented the development of TEVG stenosis. Our results provide support for pharmacologic treatment with losartan as a strategy to modulate monocyte infiltration into the grafts and thus prevent TEVG stenosis.-Ruiz-Rosado, J. D. D., Lee, Y.-U., Mahler, N., Yi, T., Robledo-Avila, F., Martinez-Saucedo, D., Lee, A. Y., Shoji, T., Heuer, E., Yates, A. R., Pober, J. S., Shinoka, T., Partida-Sanchez, S., Breuer, C. K. Angiotensin II receptor I blockade prevents stenosis of tissue engineered vascular grafts.
我们之前研发了一种组织工程血管移植物（TEVG），其制作方法是将自体细胞接种到可生物降解的管状支架上，旨在制造一种具有生长潜力的活体血管移植物，用于接受先天性心脏手术的儿童。我们的临床试验结果表明，TEVG具有生长能力，但由于TEVG狭窄的发生率较高，目前尚不建议广泛应用于临床。在动物模型中，TEVG狭窄是由单核细胞募集增加及其经典（“M1”）激活所致。在此，我们报告这些单核细胞的来源及调控机制。将TEVG植入野生型、CCR2基因敲除（Ccr2）、脾切除及脾移植受体小鼠体内。我们发现，在新血管形成急性期，从脾脏隔离中释放出来的骨髓源性Ly6C单核细胞是浸润TEVG的单核细胞的来源。此外，短期给予氯沙坦（0.6 g/L，2周），一种血管紧张素II 1型受体拮抗剂，可显著减少支架内的巨噬细胞群体（Ly6C/F480），并改善TEVG的长期通畅性。值得注意的是，骨髓源性单核细胞接种与短期氯沙坦治疗的联合作用完全预防了TEVG狭窄的发生。我们的结果支持将氯沙坦作为一种药理治疗策略，以调节单核细胞向移植物内的浸润，从而预防TEVG狭窄。-鲁伊斯 - 罗萨多，J.D.D.，李，Y.-U.，马勒，N.，易，T.，罗夫莱多 - 阿维拉，F.，马丁内斯 - 绍塞多，D.，李，A.Y.，庄司，T.，豪尔，E.，耶茨，A.R.，波伯，J.S.，筱野，T.，帕蒂达 - 桑切斯，S.，布勒，C.K.血管紧张素II受体I阻断预防组织工程血管移植物狭窄。
