Han Edward X, Qian Hong, Jiang Bo, Figetakis Maria, Kosyakova Natalia, Tellides George, Niklason Laura E, Chang William G
Department of Biomedical Engineering, Yale School of Engineering and Applied Science, New Haven, CT, USA.
Department of Anesthesiology, Yale School of Medicine, New Haven, CT, USA.
NPJ Regen Med. 2021 Jul 29;6(1):40. doi: 10.1038/s41536-021-00150-2.
A significant barrier to implementation of cell-based therapies is providing adequate vascularization to provide oxygen and nutrients. Here we describe an approach for cell transplantation termed the Therapeutic Vascular Conduit (TVC), which uses an acellular vessel as a scaffold for a hydrogel sheath containing cells designed to secrete a therapeutic protein. The TVC can be directly anastomosed as a vascular graft. Modeling supports the concept that the TVC allows oxygenated blood to flow in close proximity to the transplanted cells to prevent hypoxia. As a proof-of-principle study, we used erythropoietin (EPO) as a model therapeutic protein. If implanted as an arteriovenous vascular graft, such a construct could serve a dual role as an EPO delivery platform and hemodialysis access for patients with end-stage renal disease. When implanted into nude rats, TVCs containing EPO-secreting fibroblasts were able to increase serum EPO and hemoglobin levels for up to 4 weeks. However, constitutive EPO expression resulted in macrophage infiltration and luminal obstruction of the TVC, thus limiting longer-term efficacy. Follow-up in vitro studies support the hypothesis that EPO also functions to recruit macrophages. The TVC is a promising approach to cell-based therapeutic delivery that has the potential to overcome the oxygenation barrier to large-scale cellular implantation and could thus be used for a myriad of clinical disorders. However, a complete understanding of the biological effects of the selected therapeutic is absolutely essential.
细胞疗法实施的一个重大障碍是提供充足的血管化以供应氧气和营养物质。在此，我们描述一种细胞移植方法，称为治疗性血管导管（TVC），它使用无细胞血管作为含有设计用于分泌治疗性蛋白质的细胞的水凝胶鞘的支架。TVC可作为血管移植物直接进行吻合。模型支持这样的概念，即TVC允许含氧血液在移植细胞附近流动以防止缺氧。作为原理验证研究，我们使用促红细胞生成素（EPO）作为模型治疗性蛋白质。如果作为动静脉血管移植物植入，这样的构建体可作为EPO递送平台和终末期肾病患者的血液透析通路发挥双重作用。当植入裸鼠体内时，含有分泌EPO的成纤维细胞的TVC能够使血清EPO和血红蛋白水平升高长达4周。然而，EPO的组成型表达导致巨噬细胞浸润和TVC管腔阻塞，从而限制了长期疗效。后续的体外研究支持EPO也具有招募巨噬细胞功能的假说。TVC是一种有前景的基于细胞的治疗递送方法，有潜力克服大规模细胞植入的氧合障碍，因此可用于多种临床疾病。然而，对所选治疗方法的生物学效应有全面的了解绝对至关重要。
