p27Kip1 Inactivation Provides a Proliferative Advantage to Transplanted Hepatocytes in DPPIV/Rag2 Double Knockout Mice after Repeated Host Liver Injury

Ray Hwang Yuan, Atsushi Ogawa, Emi Ogawa, David S. Neufeld, Liang Zhu, David A. Shafritz

Research output: Contribution to journalArticle

29 Citations (Scopus)

Abstract

Studies were conducted to develop a new DPPIV-/-Rag2 -/- mouse model for hepatocyte transplantation by allogeneic and xenogeneic cells and to compare the proliferative capacity of p27 null hepatocytes versus normal hepatocytes in this system. Dipeptidyl peptidase IV (DPPIV) gene knockout mice, in which wild-type (wt) DPPIV+ donor hepatocytes can be readily identified by enzyme histochemistry, were bred with Rag2 null mice to prepare immunotolerant DPPIV-/-/Rag2-/- double knockout mice. DPPIV-/-/Rag-/- mice were transplanted with wt hepatocytes or p27 null mouse hepatocytes, which show enhanced cell cycle activity due to disruption of the Kip1 cyclin kinase inhibitor gene, and liver repopulation was assessed under nonproliferative versus proliferative experimental conditions. After their initial engraftment, transplanted wt hepatocytes did not proliferate in untreated livers or increase significantly in response to an acute liver regenerative stimulus. p27 null hepatocytes engrafted with the same efficiency as wt hepatocytes, but showed a noticeable, although not statistically significant, increase in proliferation in response to partial hepatectomy or acute CCl4 administration. Repeated treatments with CCl4 substantially increased proliferation and liver repopulation by p27 null hepatocytes but not by wt hepatocytes. These results suggest that p27 gene inactivation does not overcome proliferative restrictions imposed on hepatocytes by the normal liver, but that after repeated episodes of toxic liver injury, the augmented proliferative capacity of p27 null hepatocytes leads to significant liver repopulation compared with wt hepatocytes. These properties of p27-deficient hepatocytes could prove useful as a target for liver repopulation in patients with intermittent or a low level of chronic liver injury.

Original languageEnglish (US)
Pages (from-to)907-919
Number of pages13
JournalCell Transplantation
Volume12
Issue number8
StatePublished - 2004

Fingerprint

Dipeptidyl Peptidase 4
Knockout Mice
Liver
Hepatocytes
Wounds and Injuries
Genes
Peptide Hydrolases
Gene Knockout Techniques
Cyclins
Poisons
Homologous Transplantation
Hepatectomy
Gene Silencing

Keywords

  • Hepatocyte transplantation
  • Kip 1
  • Liver injury
  • p27 null hepatocytes
  • Proliferation

ASJC Scopus subject areas

  • Cell Biology
  • Transplantation

Cite this

p27Kip1 Inactivation Provides a Proliferative Advantage to Transplanted Hepatocytes in DPPIV/Rag2 Double Knockout Mice after Repeated Host Liver Injury. / Yuan, Ray Hwang; Ogawa, Atsushi; Ogawa, Emi; Neufeld, David S.; Zhu, Liang; Shafritz, David A.

In: Cell Transplantation, Vol. 12, No. 8, 2004, p. 907-919.

Research output: Contribution to journalArticle

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