Bioengineer a humanized Autonomic Neurovascular Innervation on a Chip

总结 大量的静脉移植物在5年后失效，导致患者的发病率和死亡率 接受静脉移植手术静脉移植物成功适应动脉血流动力学是成功的关键。 临床效果满意。然而，静脉移植物在动脉循环下不会成为动脉。的 静脉移植物对动脉血流动力学的不完全适应可能是静脉移植物失败的主要原因。 静脉移植物中缺少的一个环节是缺乏神经支配，而动脉与神经支配密切相关。 交感神经/副交感神经最近一项关于胚胎发育的研究表明， 交感神经支配通过释放交感神经对动脉的正常发育至关重要 神经递质，提出了一个令人兴奋的可能性，即为静脉移植物提供神经支配可能有助于神经递质的分泌。 更好地将静脉转换为动脉，从而可能导致更好的临床结局。为了探索这种可能性， 在这里，我们建议检查自主神经源性信号对血管内皮动脉化的影响， 细胞（EC）及其对平滑肌细胞（SMC）表型的影响，通过建立一种新的人源化 微生理芯片上的血管神经支配模型。在该模型中，交感神经/副交感神经元， 血管内皮细胞和平滑肌细胞将被共培养，神经活动将被精确地 通过光遗传学工具控制。我们将研究交感神经/副交感神经刺激对 内皮细胞的动脉分化和平滑肌细胞的表型调节。这项研究将产生根本性的 了解自主神经信号对血管细胞命运的影响，从而对开发新的 改善血管移植物动脉化的方法。

SUMMARY A significant amount of vein grafts fail after 5 years, which leads to the morbidity and mortality of patients receiving vein graft procedures. Successful adaptation of vein grafts to arterial hemodynamics is the key to a satisfactory clinical outcome. Nevertheless, vein grafts do not become an artery under arterial circulation. The incomplete adaptation of vein grafts to arterial hemodynamics may be the primary reason of vein graft failure. One of the missing links in the vein graft is the lack of innervation, whereas arteries are closely associated with the sympathetic/parasympathetic nerves. A recent study in embryonic development suggested that sympathetic innervation is critical for the proper development of arteries through releasing sympathetic neurotransmitters, raising an exciting possibility that providing innervation to the vein graft may facilitate the better switch of vein to artery, thus potentially leading to better clinical outcomes. To explore this possibility, here we propose to examine autonomic neural derived signals on the arterialization of vascular endothelial cells (ECs) and their impact on smooth muscle cells (SMC) phenotypes, by establishing a novel humanized vascular innervation model on a microphysiological chip. In this model, sympathetic/parasympathetic neurons, vascular endothelial cells and smooth muscle cells will be co-cultured and neural activity will be precisely controlled via optogenetic tools. We will study the impact of sympathetic/parasympathetic stimulation on the arterial differentiation of ECs and phenotypic modulation of SMCs. This research will generate fundamental knowledge on autonomic nerve signals on vascular cell fate, thereby having a direct impact on developing new methods to improve arterialization of vascular grafts.