Amphiregulin stimulates liver regeneration after small-for-size mouse liver transplantation

Q. Liu, H. Rehman, Y. Krishnasamy, K. Haque, R. G. Schnellmann, J. J. Lemasters, Z. Zhong

Research output: Contribution to journalArticlepeer-review

18 Scopus citations


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. Suppressed regeneration of small-for-size liver grafts is associated with decreased amphiregulin synthesis after mouse liver transplantation, and supplementation of amphiregulin improves the outcome of small-for-size liver transplantation.

Original languageEnglish (US)
Pages (from-to)2052-2061
Number of pages10
JournalAmerican Journal of Transplantation
Issue number8
StatePublished - Aug 2012
Externally publishedYes


  • Growth factor
  • liver graft survival
  • liver regeneration
  • liver transplantation
  • living donor transplantation
  • small-for-size syndrome

ASJC Scopus subject areas

  • Immunology and Allergy
  • Transplantation
  • Pharmacology (medical)


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