Liver disease is an expanding clinical challenge that progresses patients into a state of liver failure. Liver transplantation is the only curative optio for liver failure to date. However, there is a severe shortage of liver organs for transplantation raising a dire need to develop alternative liver tissues in vitro to bridge this shortage. Liver tisue engineering is a potential solution to this problem;however numerous challenges including hepatocyte viability, nutrient limitations and phenotypic stability of the tissue plague progressio of artificial livers as a therapeutic option. Specifically, liver cells rapidly lose their physioloical phenotype and function compromising the stability and viability of the engineered liver tissue. A combination of microenvironmental factors such as spatial organization, extracellular matrix cues and stromal support through cell-cell interaction have been shown to partially stabilize their phenotype. Clearly, however, the in vivo liver environment has not been fully recapitulated and thus molecular stabilizing cues are still missing. This proposal hypothesizes a novel mode of cell-cell communication mediated by exosomes, secreted nanovesicles that transports genetic information including mRNA, microRNA and protein, can stabilize the physiological function and viability of engineered liver tissue. To date, exosome communication has not been explored in tissue engineering, however, in other systems exosome cargo modulates phenotypic behaviors in recipient cell populations by altering their translational profile to induce cellular behaviors nd processes such as proliferation, differentiation and angiogenesis. We propose to ascertain whether exosome cues present in the liver, as it develops in vivo, can be used to artificially reconstruct more stable livers in vitro. Therefore, we will use a systematic approach to profile mRNA and microRNA exosome cargo in a cell type-specific manner from developing liver in vivo and in 3-dimensional (3D) engineered liver tissue in vitro. We will screen for unique embryonic exosome cargo that are absent in 3D engineered liver tissue. We will then introduce the unique embryonic cargo into 3D engineered liver tissue in a cell type specific manner and assess its affect on phenotypic stability, function and vascular morphogenesis. The goal of this proposed work is to enhance the phenotypic stability and function of engineered liver tissue for the ultimate goal of designing an artificial liver for transplantation.

Public Health Relevance

With liver disease increasing in the human population, there is a great need to build artificial liver tissue for transplantation. In this proposal, we will expore the genetic contents of naturally occurring nanometer-sized vesicles called exosomes in the developing liver. We will then use these exosome vesicles to deliver genetic cargo found in the developing liver to artificial engineered liver in effort to improve their function for transplantaion.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Postdoctoral Individual National Research Service Award (F32)
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Special Emphasis Panel (ZDK1-GRB-2 (J1))
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Podskalny, Judith M,
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Massachusetts Institute of Technology
Other Domestic Higher Education
United States
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Stevens, K R; Ungrin, M D; Schwartz, R E et al. (2013) InVERT molding for scalable control of tissue microarchitecture. Nat Commun 4:1847