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Amphiregulin Stimulates Liver Regeneration After Small‐for‐Size Mouse Liver Transplantation
Author(s) -
Liu Q.,
Rehman H.,
Krishnasamy Y.,
Haque K.,
Schnellmann R. G.,
Lemasters J. J.,
Zhong Z.
Publication year - 2012
Publication title -
american journal of transplantation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.89
H-Index - 188
eISSN - 1600-6143
pISSN - 1600-6135
DOI - 10.1111/j.1600-6143.2012.04069.x
Subject(s) - amphiregulin , liver regeneration , transplantation , cancer research , regeneration (biology) , medicine , epidermal growth factor receptor , liver transplantation , bromodeoxyuridine , endocrinology , biology , andrology , pathology , microbiology and biotechnology , receptor , immunohistochemistry
This study investigated whether amphiregulin (AR), a ligand of the epidermal growth factor receptor (EGFR), improves liver regeneration after small‐for‐size liver transplantation. Livers of male C57BL/6 mice were reduced to ∼50% and ∼30% of original sizes and transplanted. After transplantation, AR and AR mRNA increased in 50% but not in 30% grafts. 5‐Bromodeoxyuridine (BrdU) labeling, proliferating cell nuclear antigen (PCNA) expression and mitotic index increased substantially in 50% but not 30% grafts. Hyperbilirubinemia and hypoalbuminemia occurred and survival decreased after transplantation of 30% but not 50% grafts. AR neutralizing antibody blunted regeneration in 50% grafts whereas AR injection (5 μg/mouse, iv) stimulated liver regeneration, improved liver function and increased survival after transplantation of 30% grafts. Phosphorylation of EGFR and its downstream signaling molecules Akt, mTOR, p70S6K, ERK and JNK increased markedly in 50% but not 30% grafts. AR stimulated EGFR phosphorylation and its downstream signaling pathways. EGFR inhibitor PD153035 suppressed regeneration of 50% grafts and largely abrogated stimulation of regeneration of 30% grafts by AR. AR also increased cyclin D1 and cyclin E expression in 30% grafts. Together, liver regeneration is suppressed in small‐for‐size grafts, as least in part, due to decreased AR formation. AR supplementation could be a promising therapy to stimulate regeneration of partial liver grafts.