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Enhanced proliferation and differentiation of rat hepatocytes cultured with bone marrow stromal cells
Author(s) -
Mizuguchi Toru,
Hui Thomas,
Palm Kaia,
Sugiyama Nozomu,
Mitaka Toshihiro,
Demetriou Achilles A.,
Rozga Jacek
Publication year - 2001
Publication title -
journal of cellular physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.529
H-Index - 174
eISSN - 1097-4652
pISSN - 0021-9541
DOI - 10.1002/jcp.1136
Subject(s) - stromal cell , hepatocyte , bone marrow , microbiology and biotechnology , transplantation , biology , bioartificial liver device , hepatocyte growth factor , cancer research , cell therapy , stem cell , immunology , in vitro , medicine , biochemistry , receptor
Liver transplantation is the only clinically effective method of treating acute liver failure. However, wider application of this therapeutic modality is restricted primarily by shortage of donor organs. In the search for alternative methods of liver replacement therapy, investigators have focused on transplantation of normal allogeneic hepatocytes and on the development of liver support systems utilizing isolated hepatocytes. Since all human livers suitable for cell harvest are being used for transplantation, hepatocyte therapy using human tissue would require growing of cells in vitro. Unfortunately, although hepatocytes have tremendous capacity to proliferate in vivo, their ability to grow in culture is severely limited. Stromal cells from bone marrow and other blood‐forming organs have been found to support hematopoiesis. In this paper, we show that bone marrow‐derived stromal cells (BMSCs) enhance proliferation and support differentiation of rat hepatocytes in culture. Further, we demonstrate that in hepatocyte/BMSC co‐cultures, clonal expansion of small hepatocytes (SH) is increased. Using semipermeable membrane cultures, we established that direct cell–cell contact is necessary for stimulation of cell proliferation. We also show that BMSCs which are in direct contact with hepatocytes and SH colonies express Jagged1. This suggests a potential role for Notch signaling in the observed effects. Finally, we present evidence that the expression and activity of liver specific transcirption factors, CCAAT/enhancer binding proteins and liver specific key enzymes such as tryptophan 2,3‐dioxygenase, are improved in hepatocyte/BMSC co‐cultures. In conclusion, results of this study indicate that BMSCs could facilitate proliferation and differentiation of primary rat hepatocytes and their progenitors (SH) in vitro. © 2001 Wiley‐Liss, Inc.