Autocrine-Controlled Formation and Function of Tissue-Like Aggregates by Primary Hepatocytes in Micropatterned Hydrogel Arrays

Geeta Mehta

Associate Professor

mehtagee@umich.edu

3044 NCRC, Building 28

T: (734) 763-3957

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Courtney M Williams, Geeta Mehta, Shelly R Peyton, Adam S Zeiger, Vliet, KJ Van, and Linda G Griffith (2011)

TISSUE ENGINEERING PART A, 17(7-8):1055-1068.

The liver carries out a variety of essential functions regulated in partby autocrine signaling, including hepatocyte-produced growth factors andextracellular matrix (ECM). The local concentrations of autocrinefactors are governed by a balance between receptor-mediated binding atthe cell surface and diffusion into the local matrix and are thusexpected to be influenced by the dimensionality of the cell cultureenvironment. To investigate the role of growth factor and ECM-modulatedautocrine signaling in maintaining appropriate primary hepatocytesurvival, metabolic functions, and polarity, we createdthree-dimensional cultures of defined geometry using micropatternedsemisynthetic polyethylene glycol-fibrinogen hydrogels to provide amechanically compliant, nonadhesive material platform that could bemodified by cell-secreted factors. We found that in the absence ofexogenous peptide growth factors or ECM, hepatocytes retain theepidermal growth factor (EGF) receptor ligands (EGF and transforminggrowth factor-alpha) and the proto-oncogenic mesenchymal epithelialtransition factor (c-MET) ligand hepatocyte growth factor (HGF), alongwith fibronectin. Further, hepatocytes cultured in thisthree-dimensional microenvironment maintained high levels ofliver-specific functions over the 10-day culture period.Function-blocking inhibitors of alpha 5 beta 1 or EGF receptordramatically reduced cell viability and function, suggesting thatsignaling by both these receptors is needed for in vitro survival andfunction of hepatocytes in the absence of other exogenous signals.

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