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T-cadherin modulates hepatocyte functions in vitro

Salman R. Khetani^*, Alice A. Chen^*,, Barbara Ranscht and Sangeeta N. Bhatia^*,,1

^* Division of Health Sciences and Technology/Electrical Engineering and Computer Science, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA;

School of Engineering and Applied Sciences, Harvard University, Cambridge, Massachusetts, USA;

Burnham Institute for Medical Research, La Jolla, California, USA; and

Division of Medicine, Brigham & Women’s Hospital, Boston, Massachusetts, USA

¹Correspondence: Laboratory for Multiscale Regenerative Technologies, Massachusetts Institute of Technology, 77 Massachusetts Ave., E19–502D, Cambridge, MA 02139, USA. E-mail: sbhatia{at}mit.edu

Primary hepatocytes from several different species rapidly lose viability and phenotypic functions on isolation from their native microenvironment of the liver. Stromal cells derived from both within and outside the liver can induce phenotypic functions in primary hepatocytes in vitro; however, the molecular mediators underlying this "coculture effect" have not been fully elucidated. We have previously developed a functional genomic screen utilizing cocultures of hepatocytes and 3T3 fibroblasts to identify such candidate hepatocyte-function-inducing molecules. In particular, truncated-cadherin (T-cadherin) was identified as a potential molecule of interest in induction of hepatic functions. Here we demonstrate that liver-specific functions of primary rat hepatocytes are induced on cocultivation with Chinese hamster ovary cells engineered to express T-cadherin on their surface as compared with wild-type controls. Additionally, culture of cells on substrata presenting recombinant T-cadherin protein (acellular presentation) enhanced hepatic functions in both pure hepatocyte cultures and in hepatocyte-stromal cocultures lacking endogenous T-cadherin expression. Collectively, these data indicate that both cellular and acellular presentation of T-cadherin can be used to modulate the hepatocyte phenotype in vitro for tissue engineering applications. Our work suggests potential avenues for investigating the role of T-cadherin on hepatocellular function in vivo in settings such as embryogenesis and liver pathology.—Khetani, S. R., Chen, A. A., Ranscht, B., Bhatia, S. N. T-cadherin modulates hepatocyte functions in vitro.

Key Words: CHO • fibroblasts • coculture • cytochrome P450