Scientific Poster

Evaluating Liver Disease in NASH B6 Mice

In this scientific poster, MASH development and onset of fibrosis were monitored in Taconic's B6NTac mice fed an Amylin liver NASH (aka GAN) diet. Liver biopsies have long been the gold standard for assessing MASH progression, but they are not practical for monitoring disease progression. This study demonstrates how automated shear wave elastography can be used as a minimally invasive tool to assess MASH and fibrosis onset in commercially available NASH B6 mice.

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Non-invasive staging of liver disease in C57BL/6NTac mice preconditioned on the modified-Amylin NASH diet using automated shear wave elastography

 

Laura Griffina, Steve Yeungb, Sridhar Radhakrishnanb, Christopher J. Moorec, Juan D. Rojasc, Brian Velascod, Paul A. Daytond, Tomek J. Czernuszewiczc,d
aTaconic Biosciences, Inc., Rensselaer, NY, USA, bResearch Diets, Inc., New Brunswick, NJ, USA, cRevvity, Inc., Durham, NC, USA, dUniversity of North Carolina Chapel Hill, Chapel Hill, NC, USA

Jump to: Background | Conclusions

Background

  • B6NTac fed a modified Amylin liver NASH (aka GAN) diet demonstrate SLD and more closely recapitulate human MASLD compared to other preclinical models.
  • Despite superior translatability, inherent variability exists and can only be assessed via invasive procedures (liver biopsy). Induction timeframes to fibrosis are also lengthy (>30 weeks on diet).
  • Non-invasive tools for humans exist, but these tools have not been entirely validated in preclinical research.

Aims

  1. To validate automated shear wave elastography as a tool to asses MASH and fibrosis onset in commercialy available NASH B6 mice
  2. To assess variability in MASH onset in NASH B6 mice
  3. To assess whether repeated SWE imaging may induce stress responses in the model, leading to altered phenotype regression

 

Imaging Methods

Figure 1

Fig 1. Schematic overview of image acquisition approach. A: Rodents are placed on the ultrasound instrument in prone position and imaged from below via robotically controlled raster scan. Raw 2D frames are reconstructed into 3D volumes. B: Photograph of Vega ultrasound in vivo imaging system. C: Screenshot of multi-modal 3D B-mode and SWE scan of a mouse liver in orthoslice view. D: Screenshot showing output of AI-assisted 3D liver segmentation (yellow outline). Segmentation is used to quantify liver volume, liver stiffness, and liver echogenicity.

Study Design

figure 2

Fig 2. Overview of animal cohorts and experimental timeline. NASH B6 animals were shipped from Taconic Biosciences to UNC, where they were acclimated on respective diets and underwent SWE measurement at specifi c experimental timepoints.

Representative In Vivo Images

figure 3

Fig 3. Representative images of mice on Control diet (top row) and NASH chow (bottom row). Anatomical B-mode images are shown in grayscale, while SWE stiffness maps are overlaid with blue-red colormap. Over time, NASH livers were signifi cantly larger and brighter than controls, indicating hepatomegaly and steatosis. Liver stiffness in NASH livers was marginally higher, suggesting limited fi brosis.

Longitudinal In Vivo Measurements 

liver volume
echogenicity
stiffness

Figure 4. Liver volume, echogenicity, and stiffness measurements quantifi ed from in vivo images over time. Both liver volume and echogenicity were signifi cantly higher in NASH cohort compared to controls from fi rst timepoint at 13 weeks, and increased considerably over time (2.2-fold and 1.3-fold for volume and echogenicity, respectively). Liver stiffness started to increase marginally after 24 WOD. Wilcoxon rank sum; * P≤0.05; ** P≤0.01

Cross-Sectional In Vivo Measurements

figure 4

Fig 5. Liver volume, echogenicity, and stiffness measurements quantified in cross-sectional cohort. Nearly identical trends were observed as in longitudinal cohort; namely, volume and echogenicity were much higher than controls, while stiffness was marginally higher. Matched timepoints at 16 and 26 weeks between longitudinal and cross-sectional cohorts showed non-signifi cant measurements across the board, suggesting no infl uence of serial imaging on biological progression of SLD. 

AI-Assisted In Vivo vs. Ex Vivo Comparison

figure 4

Fig 6. Bar plot (left) shows ex vivo liver weight for cross-sectional cohort, and scatter plot (right) shows comparison of in vivo liver volume to ex vivo liver weight. In vivo measurements consistently underestimated ground truth ex vivo values by ~0.5 cm³, however strong correlation (R2 = 0.88) was observed despite this bias. 

Conclusions

  • Commercially available NASH B6 mice from Taconic Biosciences demonstrated signifi cantly increased liver volume and liver echogenicity, compared to age-matched controls, consistent with time on diet.
  • Liver stiffness was marginally increased compared to age matched controls, suggesting limited fi brosis development.
  • Repeated Vega measurements did not signifi cantly alter phenotype progression in NASH B6 mice.
  • Low-fat purifi ed control diets may induce liver steatosis, as indicated by increases in liver echogenicity over time.
  • Vega may be a useful tool for screening and randomization of animals based on liver volume, steatosis onset, and fi brosis stage in preclinical drug testing.
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