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.

National Institute of Health (NIH)
National Institute of Biomedical Imaging and Bioengineering (NIBIB)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZEB1-OSR-D (J1))
Program Officer
Hunziker, Rosemarie
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Pennsylvania
Biomedical Engineering
Schools of Engineering
United States
Zip Code
Lee, Esak; Song, H-H Greco; Chen, Christopher S (2016) Biomimetic on-a-chip platforms for studying cancer metastasis. Curr Opin Chem Eng 11:20-27
Rezza, Amélie; Wang, Zichen; Sennett, Rachel et al. (2016) Signaling Networks among Stem Cell Precursors, Transit-Amplifying Progenitors, and their Niche in Developing Hair Follicles. Cell Rep 14:3001-18
Kutys, Matthew L; Chen, Christopher S (2016) Forces and mechanotransduction in 3D vascular biology. Curr Opin Cell Biol 42:73-79
Stevens, Kelly R; Miller, Jordan S; Blakely, Brandon L et al. (2015) Degradable hydrogels derived from PEG-diacrylamide for hepatic tissue engineering. J Biomed Mater Res A 103:3331-8
Chaturvedi, Ritika R; Stevens, Kelly R; Solorzano, Ricardo D et al. (2015) Patterning vascular networks in vivo for tissue engineering applications. Tissue Eng Part C Methods 21:509-17
Rodriguez, Natalia M; Desai, Ravi A; Trappmann, Britta et al. (2014) Micropatterned multicolor dynamically adhesive substrates to control cell adhesion and multicellular organization. Langmuir 30:1327-35
Galie, Peter A; Nguyen, Duc-Huy T; Choi, Colin K et al. (2014) Fluid shear stress threshold regulates angiogenic sprouting. Proc Natl Acad Sci U S A 111:7968-73
Bhatia, Sangeeta N; Underhill, Gregory H; Zaret, Kenneth S et al. (2014) Cell and tissue engineering for liver disease. Sci Transl Med 6:245sr2
Desai, Ravi A; Rodriguez, Natalia M; Chen, Christopher S (2014) ""Stamp-off"" to micropattern sparse, multicomponent features. Methods Cell Biol 119:3-16
Li, Cheri Y; Stevens, Kelly R; Schwartz, Robert E et al. (2014) Micropatterned cell-cell interactions enable functional encapsulation of primary hepatocytes in hydrogel microtissues. Tissue Eng Part A 20:2200-12

Showing the most recent 10 out of 31 publications