Single-Cell Transcriptome Analysis of Mouse Liver Cell-Specific Tropism and Transcriptional Dysregulation Following Intravenous Administration of AAVrh.10 Vectors.

Human Gene Therapy
Detu ZhuRonald G Crystal

Abstract

Capitalizing on liver tropism of adeno-associated viral (AAV) vectors, intravenous vector administration is commonly used to genetically modify hepatocytes, a strategy currently in clinical trials for a number of liver-based hereditary disorders. Although hepatocytes are known to exhibit extensive phenotypic heterogeneity influenced by liver zonation and dietary cycle, there is little data available for the tropism capacity, as well as the potential transcriptional dysregulation, of AAV vectors for specific liver cell types. To assess these issues, we employed single-cell RNA sequencing of the mouse liver after intravenous administration of the liver tropic AAVrh.10 vector to characterize cell-specific AAV-mediated transgene expression and transcriptome dysregulation. Wild-type 8-week-old male C57Bl/6 mice under normal feed cycle were randomly divided into three groups and intravenously administered phosphate-buffered saline (PBS), AAVrh.10Null (no transgene), or AAVrh.10mCherry (marker gene). Overall, a total of 46,500 liver cells were sequenced. The single-cell transcriptomic profiles were grouped into three separate clusters of hepatocytes (Ttr-enriched "Hep1," Tat-enriched "Hep2," and Alb-enriched "Hep3") and multiple other...Continue Reading

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Methods Mentioned

BETA
single-cell sequencing

Software Mentioned

Seurat
Seurat R

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