Synthetic vascularization and regeneration in engineered tissues

项目说明 这个新项目的目标是设计肝组织移植，在这种情况下，时间和范围 移植物在活体宿主体内的血管化和扩张的程度是可以直接操作的。在体内，细胞到细胞 通过旁分泌信号进行的交流是多细胞生命的标志，而在 肝脏被认为在推动组织血管形成和生长方面发挥着关键作用。在协作中 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整合在一起，形成空间图案以支持这些 细胞与细胞的相互作用。这些相互作用使血管再生和扩张成为可能 在体外，在微流控人肝模型中，以及在体内，在 一种异位植入的人肝移植。在这项提案中，调查人员将在 这些模型系统通过利用合成的转录因子控制 工程肝脏内旁分泌信号的动态变化，以实现受控的、按需的 组织血管化和扩张。这项新建议的具体目标是：(1)建设 通过合成血管化在工程组织中形成功能性血管，(2)建立 通过合成再生按需扩增工程化功能性肝组织，以及 (3)开发次优主机下的系统集成和健壮性方法 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综合防治方法 工程化组织将推动工程化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.