Morphological and microarray analyses of human hepatocytes from xenogeneic host livers

Chise Tateno, Fuyuki Miya, Kenjiro Wake, Miho Kataoka, Yuji Ishida, Chihiro Yamasaki, Ami Yanagi, Masakazu Kakuni, Eddie Wisse, Fons Verheyen, Kouji Inoue, Kota Sato, Atsushi Kudo, Shigeki Arii, Toshiyuki Itamoto, Toshimasa Asahara, Tatsuhiko Tsunoda, Katsutoshi Yoshizato

Research output: Contribution to journalArticlepeer-review

50 Citations (Scopus)

Abstract

We previously produced mice with human hepatocyte (h-hep) chimeric livers by transplanting h-heps into albumin enhancer/promoter-driven urokinase-type plasminogen activator-transgenic severe combined immunodeficient (SCID) mice with liver disease. The chimeric livers were constructed with h-heps, mouse hepatocytes, and mouse hepatic sinusoidal cells (m-HSCs). Here, we investigated the morphological features of the chimeric livers and the h-hep gene expression profiles in the xenogeneic animal body. To do so, we performed immunohistochemistry, morphometric analyses, and electron microscopic observations on chimeric mouse livers, and used microarray analyses to compare gene expression patterns in hepatocytes derived from chimeric mouse hepatocytes (c-heps) and h-heps. Morphometric analysis revealed that the ratio of hepatocytes to m-HSCs in the chimeric mouse livers were twofold higher than those in the SCID mouse livers, corresponding to twin-cell plates in the chimeric mouse liver. The h-heps in the chimeric mouse did not show hypoxia even in the twin-cell plate structure, probably because of low oxygen consumption by the h-heps relative to the mouse hepatocytes (m-heps). Immunohistochemical and electron microscopic examinations revealed that the sinusoids in the chimeric mouse livers were normally constructed with h-heps and m-HSCs. However, a number of microvilli projected into the intercellular clefts on the lateral aspects of the hepatocytes, features typical of a growth phase. Microarray profiles indicated that ∼82% of 16 605 probes were within a twofold range difference between h-heps and c-heps. Cluster and principal component analyses showed that the gene expression patterns of c-heps were extremely similar to those of h-heps. In conclusion, the chimeric mouse livers were normally reconstructed with h-heps and m-HSCs, and expressed most human genes at levels similar to those in human livers, although the chimeric livers showed morphological characteristics typical of growth.

Original languageEnglish
Pages (from-to)54-71
Number of pages18
JournalLaboratory Investigation
Volume93
Issue number1
DOIs
Publication statusPublished - 2013 Jan
Externally publishedYes

Keywords

  • human hepatocytes
  • microarray
  • ultrastructure
  • uPA/SCID mouse

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Molecular Biology
  • Cell Biology

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