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Journal of Integrative Medicine ›› 2014, Vol. 12 ›› Issue (1): 20-34.doi: 10.1016/S2095-4964(14)60003-0

• Research Article • Previous Articles     Next Articles

Pristimerin enhances recombinant adeno-associated virus vector-mediated transgene expression in human cell lines in vitro and murine hepatocytes in vivo

Li-na Wanga,b,c, Yuan Wanga,b,c,d, Yuan Lue, Zi-fei Yina, Yuan-hui Zhanga,b,c,d, George V. Aslanidib,c, Arun Srivastavab,c,f,g,h, Chang-quan Linga,d, Chen Lingb,c   

  1. Changhai Hospital of Traditional Chinese Medicine, Second Military Medical University, Shanghai 200433, China
    Division of Cellular and Molecular Therapy, Department of Pediatrics, University of Florida College of Medicine, Gainesville, Florida 32611, USA
    Powell Gene Therapy Center, University of Florida College of Medicine, Gainesville, Florida 32611, USA
    Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
    Department of Orthopaedics and Rehabilitation, University of Florida College of Medicine, Gainesville,Florida 32611, USA
    Department of Molecular Genetics and Microbiology, University of Florida College of Medicine, Gainesville, Florida 32611, USA
    Genetics Institute, University of Florida College of Medicine, Gainesville, Florida 32611, USA
    Shands Cancer Center, University of Florida College of Medicine, Gainesville, Florida 32611, USA
  • Received:2013-07-22 Accepted:2013-08-27 Online:2014-01-10 Published:2014-01-15

Objective

In the present study, we systemically evaluated the ability of two bioactive compounds from traditional Chinese medicine, celastrol and pristimerin, to enhance recombinant adeno-associated virus (rAAV) serotype vector-mediated transgene expression both in human cell lines in vitro, and in murine hepatocytes in vivo.
Methods

Human cell lines were infected with rAAV vectors with either mock treatment or treatment with celastrol or pristimerin. The transgene expression, percentage of nuclear translocated viral genomes and the ubiquitination of intracellular proteins were investigated post-treatment. In addition, nonobese diabetic/severe combined immunodeficient gamma (NSG) mice were tail vain-injected with rAAV vectors and co-administered with either dimethyl sulfoxide, celastrol, pristimerin or a positive control, bortezomib. The transgene expression in liver was detected and compared over time. 

Results

We observed that treatment with pristimerin, at as low as 1 μmol/L concentration, significantly enhanced rAAV2 vector-mediated transgene expression in vitro, and intraperitoneal co-administration with pristimerin at 4 mg/(kg·d) for 3 d dramatically facilitated viral transduction in murine hepatocytes in vivo. The transduction efficiency of the tyrosine-mutant rAAV2 vectors as well as that of rAAV8 vectors carrying oversized transgene cassette was also augmented significantly by pristimerin. The underlying molecular mechanisms by which pristimerin mediated the observed increase in the transduction efficiency of rAAV vectors include both inhibition of proteasomal degradation of the intracellular proteins and enhanced nuclear translocation of the vector genomes. Conclusion

These studies suggest the potential beneficial use of pristimerin and pristimerin-containing herb extract in future liver-targeted gene therapy with rAAV vectors.

Key words: Celastrol, Pristimerin, Adeno-associated viral vector, Proteosomal inhibitor, Gene therapy

Figure 1

Schematic outline of chemical compounds and viral genomesA: The chemical structure of celastrol and pristimerin. B: Schematic structures of rAAV2 vectors containing various indicated rAAV vector genomes. sc: self-complementary; ss: single-stranded; AAV: adeno-associated virus; CBAp: chicken β-actin/cytomegalovirus enhancer hybrid promoter; EGFP: enhanced green fluorescence protein; EYFP: enhanced yellow fluorescence protein; HP: hairpin structure; HP-: hairpin structure without terminal resolution site; hGH: human growth hormone."

Figure 2

Celastrol modestly enhanced rAAV2-mediated transduction efficiency HeLa cells were treated with celastrol for 2 h, followed by infection with scAAV2-CB-EGFP vectors at multiplicity of infection of 5 000 viral genomes/cell with or without celastrol. All transgene expression was detected by fluorescence microscopy 72 h post-transduction and was analyzed quantitatively by ImageJ analysis software. Transgene expression was assessed as total area of green fluorescence (pixel2) per visual field. Data are expressed as mean ± standard deviation, n= 3; **P<0.01, vs DMSO group.rAAV: recombinant adeno-associated virus; PBS: phosphate-buffered saline; DMSO: dimethyl sulfoxide."

Figure 3

Cell viability assays to determine IC50 of celastrol and pristimerin HeLa cells were exposed to different concentrations of celastrol or pristimerin for 4 h and then were cultured in complete Dulbecco’s modified Eagle medium without drugs for additional 20 h, followed by cell cytotoxicity assays using Cell Counting Kit-8.IC50: half maximal inhibitory concentration."

Figure 4

Pristimerin significantly enhanced rAAV2-mediated transgene expression in vitro A: Various doses of celastrol (1, 2.5 and 5 μmol/L) and pristimerin (0.5, 1 and 2.5 μmol/L) were co-administered with scAAV2-CBAp-EGFP (5 000 viral genomes/cell) vector to transduce HeLa cells. B: Transgene expression was detected by flow cytometry 72 h post-transduction from Figure 4A. C: Various doses of celastrol and pristimerin, as Figure 4A, were co-administered with high dose of scAAV2-CBAp-EGFP (50 000 viral genomes/cell) vector to transduce HeLa cells. D: Huh7 cells were treated with indicated drugs for 2 h, followed by infection with scAAV2-CBAp-EGFP vectors at 20 000 viral genomes/cell with or without drug treatment. All transgene expression was detected by fluorescence microscopy 72 h post-transduction and was analyzed quantitatively by ImageJ analysis software. Transgene expression was assessed as total area of green fluorescence (pixel2) per visual field. Data are expressed as mean ± standard deviation, n=3; **P<0.01, vs DMSO group; △△P<0.01, vs celastrol (1 μmol/L) group.rAAV: recombinant adeno-associated virus; DMSO: dimethyl sulfoxide. scAAV2-CBAp-EGFP: self-complementary adeno-associated virus 2-chicken β-actin/cytomegalovirus enhancer hybrid promoter-enhanced green fluorescence protein."

Figure 5

Total RNAs from HeLa cells were extracted 24 h post-infection with scAAV2 vectors RNAs were subjected to reverse transcription using oligo-d(T) primers, and subsequent qRT-PCR assays specific for enhanced green fluorescence protein. Data are expressed as mean ± standard deviation, n=3; *P<0.05, **P<0.01, vs DMSO group scAAV: self-complementary adeno-associated virus; qRT-PCR: quantitativereverse transcriptase-polymerase chain reaction; DMSO: dimethyl sulfoxide."

Figure 6

Pristimerin acted at a step post-viral entry A: Western blot assays showing the purity of isolated cellular fraction. B: Normalized percentages of the distributions of scAAV2 vectors in the nuclear fractions at 16 h post-treatment of indicated drugs with scAAV2 vectors. C: Numbers of intracellular scAAV2 vector genomes at 2 h post-treatment of indicated drugs with scAAV2 vectors. Data are expressed as mean ± standard deviation, n=3; **P<0.01, vs DMSO group.scAAV: self-complementary adeno-associated virus; DMSO: dimethyl sulfoxide."

Figure 7

Subcellular localization of scAAV2-Cy3 virions 16 h after treatment of indicated drugs Images were acquired on Leica TCS SP5 confocal microscopy using oil immersed 63× objective lens.Green: nucleus; Blue: cell membrane; Red: rAAV2 particles.scAAV: self-complementary adeno-associated virus; rAAV: recombinant adeno-associated virus."

Figure 8

Accumulation of poly-ubiquitinated total cellular proteins after pristimerin treatment HeLa cells were treated with indicated drugs for 2 h, followed by infection with scAAV2-CBAp-EGFP vectors at 2 000 viral genomes/cell with or without drug treatment for 2 h. Total cellular proteins were extracted, followed by Western blot assay using specific antibodies to ubiquitin.GAPDH is served as a loading control. GAPDH: glyceraldehyde 3-phosphate dehydrogenase."

Figure 9

Pristimerin enhanced rAAV2-mediated transgene expression in vivo without change of viral tropism Six- to eight-week old male immune-deficient NSG mice were treated for 3 d with pristimerin or celastrol at a dose of 4 mg/(kg·d) or a DMSO vehicle control by intraperitoneal administration. ssAAV2-CBAp-FLuc-EYFP vectors were systemically delivered via tail vein at 1×1011 viral genomes/mouse on the second day of treatment. A: Representative images from luciferase live imaging at 2-week and 8-week post-transduction. B and C: Major organs were harvested 8 weeks after transduction and sections of major tissues were examined for EYFP expression, using a fluorescence microscope. Representative images are shown. Original magnification, B ×50 and C ×50 or ×400. D: The quantitative data of fluorescence in mice liver. E: Vector genome copy numbers in liver 8 weeks after transduction. Total DNA was isolated from 25 mg tissues and 100 ng of each was used to determine vector genome copies. Data are expressed as mean ± standard deviation, n=3; **P<0.01, vs DMSO group.ssAAV: single-stranded adeno-associated virus; rAAV: recombinant adeno-associated virus; DMSO: dimethyl sulfoxide."

Figure 10

Transduction efficiency in vivo mediated by capsid-modified ssAAV2 after pristimerin treatmentA: Representative images from luciferase live imaging at 4-week post-transduction with indicated ssAAV2 vectors and cotreatment with indicated drugs. B: Quantification data of the luciferase expression over time. Data are expressed as mean ± standard deviation, n=3; △△P<0.01, vs rAAV2-TM group; ▲▲P<0.01, vs rAAV2-WT group.ssAAV: single-stranded adeno-associated virus; rAAV: recombinant adeno-associated virus; DMSO: dimethyl sulfoxide."

Figure 11

Transduction efficiency in vivo mediated by oversized wild-type scAAV8 vectors after pristimerin treatment A: Representative images from luciferase live imaging at 4-week post-transduction with oversized scAAV8 vectors and cotreatment with indicated drugs. B: Quantification data of luciferase expression in A. Data are expressed as mean ± standard deviation, n=3; □□P<0.01, vs rAAV8 group.scAAV: self-complementary adeno-associated virus; rAAV: recombinant adeno-associated virus; DMSO: dimethyl sulfoxide."

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