Turner Mackenzie E, Che Jingru, Leland Joseph T, Villarreal Delaney J, Rajesh Sahana, Suravarapu Sugath, Hor Kan N, Wiet Matthew G, Kerlin Bryce A, Yi Tai, Best Cameron A, Reinhardt James W, Breuer Christopher K
Center for Regenerative Medicine, Research Institute at Nationwide Children's Hospital, Columbus, OH, USA.
Molecular Cellular and Developmental Biology Graduate Program, The Ohio State University, Columbus, OH, USA.
NPJ Regen Med. 2025 Jul 21;10(1):34. doi: 10.1038/s41536-025-00419-w.
The success of implanted tissue-engineered vascular grafts (TEVGs) relies on the coordinated inflammation and wound healing processes that simultaneously degrade the scaffold and guide the formation of a neovessel. Dysregulated responses can lead to aberrant remodeling (e.g., stenosis), impacting the long-term outcome and functionality of the TEVG. We developed a TEVG that, despite demonstrating growth capacity in the clinic, exhibited an unexpectedly high incidence of stenosis, or narrowing of the graft lumen. This study identified platelet-mediated immune signaling via the lysosomal trafficking regulator (Lyst) as a key driver of stenosis. Lyst mutations significantly impaired platelet dense granule exocytosis yet preserved alpha granule secretion and adhesion to the biomaterial. Uncontrolled platelet aggregation, potentiated by dense granule signaling, results in the formation of a mural thrombus that remodels into occlusive neotissue. Importantly, inhibiting sustained platelet aggregation using the P2Y12 antagonist, prasugrel, is a successful strategy for optimizing neotissue formation and improving overall TEVG performance.
植入式组织工程血管移植物（TEVG）的成功依赖于协调的炎症和伤口愈合过程，这些过程能同时降解支架并引导新血管的形成。反应失调会导致异常重塑（如狭窄），影响TEVG的长期结果和功能。我们开发了一种TEVG，尽管在临床上显示出生长能力，但却出现了出乎意料的高狭窄发生率，即移植物管腔变窄。本研究确定血小板通过溶酶体运输调节因子（Lyst）介导的免疫信号是狭窄的关键驱动因素。Lyst突变显著损害血小板致密颗粒胞吐作用，但保留α颗粒分泌和对生物材料的粘附。由致密颗粒信号增强的不受控制的血小板聚集导致壁血栓形成，进而重塑为闭塞性新组织。重要的是，使用P2Y12拮抗剂普拉格雷抑制持续的血小板聚集是优化新组织形成和改善整体TEVG性能的成功策略。
