Title: Engineering Multicellular Tissue Structure, Function, and Vascularization Abstract This project focuses on how the spatial organization of cells and resultant cell-cell interactions regulate the development and maintenance of stable tissue function within a tissue engineered construct. In vivo, cell-to- cell 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. Because the spatial organization of cells within tissues defines which juxtapositions exist between which cell types, this architecture ultimately can determine whether a tissue engineered construct ultimate will fail or succeed. Unfortunately, few tools currently exist to manipulate multicellular spatial organization;thus little is known about the true impact of tissue architecture to tissue function. The long-term goal of this project is to develop such cellular patterning tools, to use them to investigate the role of multicellular organization in regulating tissue function, and to explore how such organization can be used to enhance the function of engineered tissues. While the tools to be developed can be considered generic, the investigators will focus as a case study on the development of a vascularized engineered liver. The investigators have recently developed several multicellular patterning tools, and used them to demonstrate the importance of both hepatocyte-stromal cell- cell interactions in supporting hepatocyte function, and interactions between parenchymal and vascular compartments in driving angiogenesis. Interestingly, there appear to be relevant pairwise interactions that occur between several cell types in this setting, and involve a combination of soluble paracrine signals and direct effects through cadherin engagement. It is apparent from these early studies that careful mechanistic studies are necessary to deconvolute and understand how these multiple interactions will contribute to the vascularization and differentiated function of the liver construct, so that a rational strategy can be developed to ultimately construct a functional tissue. It is proposed that a multifaceted in vitro and in vivo effort will be required to develop the necessary tools and studies to meet these goals.
Specific Aim 1 will be to investigate the role of cell-cell interactions between hepatocytes, fibroblasts, and endothelial cells in regulating liver and angiogenic functions using several novel two-dimensional patterning tools.
Specific Aim 2 will be to investigate how the organization of cells in three-dimensional constructs affects tissue function.
Specific Aim 3 will be to explore the involvement of multicellular organization in regulating tissue integration and vascularization in an in vivo setting. In addition to novel approaches to generate patterned multi-cell type constructs, the investigators will also develop nanoparticles for non-invasive monitoring of tissue vascularization. This project will lead to an integrated understanding of the role of multicellular organization and cell-cell communication in stabilizing tissue function, and provide new tools and strategies to engineer complex multicellular tissues.

Public Health Relevance

This project will develop tools to organize multiple cell types within an engineered liver construct to maximize tissue function and integration with the patient's blood supply. 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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Biomedical Imaging and Bioengineering (NIBIB)
Type
Research Project (R01)
Project #
5R01EB008396-04
Application #
8242801
Study Section
Special Emphasis Panel (ZEB1-OSR-D (J1))
Program Officer
Hunziker, Rosemarie
Project Start
2009-06-15
Project End
2014-03-31
Budget Start
2012-04-01
Budget End
2014-03-31
Support Year
4
Fiscal Year
2012
Total Cost
$663,186
Indirect Cost
$108,572
Name
University of Pennsylvania
Department
Biomedical Engineering
Type
Schools of Engineering
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
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Desai, Ravi A; Rodriguez, Natalia M; Chen, Christopher S (2014) "Stamp-off" to micropattern sparse, multicomponent features. Methods Cell Biol 119:3-16
Li, Fengqiang; Xu, Ting; Nguyen, Duc-Huy T et al. (2014) Label-free evaluation of angiogenic sprouting in microengineered devices using ultrahigh-resolution optical coherence microscopy. J Biomed Opt 19:16006
Stevens, K R; Ungrin, M D; Schwartz, R E et al. (2013) InVERT molding for scalable control of tissue microarchitecture. Nat Commun 4:1847
Trappmann, Britta; Chen, Christopher S (2013) How cells sense extracellular matrix stiffness: a material's perspective. Curr Opin Biotechnol 24:948-53
Nguyen, Duc-Huy T; Stapleton, Sarah C; Yang, Michael T et al. (2013) Biomimetic model to reconstitute angiogenic sprouting morphogenesis in vitro. Proc Natl Acad Sci U S A 110:6712-7
Baker, Brendon M; Trappmann, Britta; Stapleton, Sarah C et al. (2013) Microfluidics embedded within extracellular matrix to define vascular architectures and pattern diffusive gradients. Lab Chip 13:3246-52
Baranski, Jan D; Chaturvedi, Ritika R; Stevens, Kelly R et al. (2013) Geometric control of vascular networks to enhance engineered tissue integration and function. Proc Natl Acad Sci U S A 110:7586-91

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