Synthetic vascularization and regeneration in engineered tissues

项目描述 这个新项目的目标是设计肝组织移植物， 移植物血管化和扩张在活体宿主中的作用是可直接操纵的。体内，细胞间 通过旁分泌信号介导的通讯是多细胞生命的标志，在 肝脏被认为在驱动组织血管形成和生长中起关键作用。协同 研究人员最近建立了肝组织的实验模型， 将肝细胞、内皮细胞和基质细胞在空间上图案化以支持这些细胞， 细胞与细胞之间的相互作用。这些相互作用使血管再生扩张， 在体外，在微流体人肝模型中，和在体内，在微流体人肝模型中， 异位移植的人类肝脏在这项提案中，调查人员将建立在 这些模型系统通过利用合成转录因子来控制 工程肝脏内的旁分泌信号动力学， 组织血管化和扩张。这项新建议的具体目标是：（1）建立 通过合成血管化在工程组织中构建功能性血管，（2）建立 通过合成再生按需扩增工程化的功能性肝组织，以及 (3)在次优主机中开发系统集成和鲁棒性的方法 环境.总之，利用体外和体内模型，这些努力将赋予 精确控制工程血管和肝脏的功能、扩张和植入 并将更普遍地建立一种新的方法，为综合控制 工程组织，将推进工程器官移植更接近临床实用。

Project Description The goal of this NEW PROJECT is to engineer liver tissue grafts in which the timing and extent of graft vascularization and expansion in a living host is directly manipulable. In vivo, cell-to-cell communication mediated through paracrine signals is a hallmark of multicellular life, and in the liver is thought to play a critical role in driving tissue vascularization and growth. In collaborative studies, the investigators have recently established experimental models of liver tissue that incorporate hepatocytes, endothelial cells, and stromal cells spatially patterned to bolster these cell-cell interactions. These interactions enable vascularization regenerative expansion of engineered human liver tissue both in vitro, in a microfluidic human liver model, and in vivo, in an ectopically implanted human liver graft. In this proposal, the investigators will build upon these model systems by leveraging synthetic transcription factors to take control over the dynamics of paracrine signaling within the engineered livers to enable controlled, on-demand tissue vascularization and expansion. The specific aims of this new proposal are: (1) To build functional vasculature in engineered tissue through synthetic vascularization, (2) To establish on-demand expansion of engineered functional liver tissue through synthetic regeneration, and (3) To develop approaches for system integration and robustness in suboptimal host environments. Together, leveraging both in vitro and in vivo models, these efforts will endow precise control of function, expansion, and engraftment of engineered vasculature and hepatic parenchyma and will more generally establish a new approach for synthetic control of engineered tissues that will advance engineered organ grafts closer towards clinical utility.