The goal of this project is to define multicellular interactions in engineered hepatic tissue that will enable its engraftment and expansion in a living host. In vivo, cell-to-cel communication and cooperation mediated through juxtacrine and paracrine signals is a hallmark of multicellular life, and is thought to play a critical role in the establishment of native tissue functions. Specifically in liver, such interactions appear to be critical for tissue function and regeneration. Unfortunately, few tools currently exist to manipulate multicellular spatial organization; thus little is known about the true impact of tissue architecture to tissue function. During the past 4 years of this collaborative project, the investigators have shown that biomaterials can be used to support the transplantation and peritoneal engraftment of human engineered artificial livers composed of randomly- organized human hepatocytes, endothelial cells and stromal cells. Then, by using novel microtechnology tools to control the organization of these cell types within a 3D context, the team has shown that architecture impacts both the differentiated state of the hepatocyte and the function of the transplanted graft. In addition, the investigators have developed bioprinting tools to build vascular networks in these 3D hydrogels and demonstrated that these improve the survival of co-embedded hepatocytes as well as methods to prevacularize hepatic tissues and thereby accelerate the peritoneal engraftment. In these model systems, we observe that there is a reciprocal interaction via paracrine signals- that is endothelial cells impact hepatocyte function and conversely that hepatocytes impact the endothelial network. Interestingly, many of the paracrine signals are interrelated with perfusion of the network as they are regulated either by shear stress, hypoxia or both. In the current application, the investigators seek to define the spatial dependence on paracrine signaling and perfusion within engineered livers that would efficiently allow them to engraft and expand upon stimulation.
The specific aims of this competitive renewal are: (1) To define the role of 3D positioning on paracrine signaling between hepatocytes and endothelial cells in vitro and in vivo, (2) To understand the role of network perfusion on cell function in 3D constructs in vitro and in vivo, and (3) To assess the functional role of network architecture and perfusion on graft expansion in vivo. This project will lead to an integrated understanding of the role of multicellulr organization and cell-cell communication in stabilizing hepatic tissue vascularization and function, and provide new tools and strategies to the broader community to engineer complex multicellular tissues.
Although engineering functional tissues and organs has major implications to address unmet demands for replacement tissue and organs, integration of blood vessels to support tissue survival and function, or `vascularization', remains a key challenge. This project will develop tools to organize these structures within the engineered constructs to maximize their function and the integration of the tissue with the patient's blood supply, and study their impact on integration and regeneration of engineered liver. As such, these studies will address several major hurdles towards the engineering of tissues for treating diseases that are otherwise only cured by whole organ transplantation.
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