Morphological and microarray analyses of human hepatocytes from xenogeneic host livers

Area of Science:

• Hepatology
• Xenotransplantation
• Animal Models

Background:

• Human hepatocyte (h-hep) chimeric livers were previously generated in urokinase-type plasminogen activator-transgenic SCID mice.
• These chimeric livers consist of human hepatocytes, mouse hepatocytes, and mouse hepatic sinusoidal cells (m-HSCs).

Purpose of the Study:

• To investigate the morphological characteristics of these chimeric livers.
• To analyze the gene expression profiles of human hepatocytes within the xenogeneic environment.

Main Methods:

• Immunohistochemistry and morphometric analyses were performed on chimeric mouse livers.
• Electron microscopy and microarray analyses were used to assess liver structure and gene expression.
• Gene expression patterns of chimeric mouse hepatocytes (c-heps) were compared to human hepatocytes (h-heps).

Main Results:

• Chimeric livers exhibited a higher hepatocyte to m-HSC ratio, forming twin-cell plates without hypoxia in h-heps.
• Sinusoids were normally constructed, and h-heps displayed microvilli indicative of a growth phase.
• Approximately 82% of genes showed similar expression levels between h-heps and c-heps, with highly similar overall gene expression patterns.

Conclusions:

• The chimeric mouse livers were successfully reconstructed with normal morphology and cellular composition.
• Human hepatocytes in chimeric livers expressed most human genes at levels comparable to human livers.
• The chimeric livers demonstrated morphological features of growth, suggesting successful integration and function of human hepatocytes.