Fibrosis Your Way

​​​Woodland Liver Fibrosis Models

 

Metabolic Diseases, NASH and Chemically-induced Liver Fibrosis

Metabolically driven NASH – 8+ options for your study 

  • Hyperglycemia, steatosis, inflammation, fibrosis, precancerous lesions

  • Standard 2-hit model (STZ + HFD) 20 weeks

  • Accelerated 2-hit model (STZ-HFD) 10 weeks*

  • 3-hit male model – added insult to increase fibrosis

  • 3-hit female model – added insult to drive fibrosis

  • DIO insulin resistant model (HFD-driven) partnered with Taconic

  • Physiological shock models

    • Gut inflammation

    • Alcohol supplemented

 

Thioacetamide (TAA)

  • Acute, chemical liver injury, approved for IP and drinking water administration

  • Typically 125-150 mg/kg IP twice (mouse) or three times (rat) per week

  • Based on Friedman, 2015 Laboratory Animals 29(S1) 21-29

Carbon Tetrachloride liver fibrosis model (CCl4)

  • Acute, chemical injury model, 6-8 weeks

  • Balb/c or C57Bl/6 mouse

  • Corn or olive oil carrier

  • IP administration twice a week (BIW)

 

Diet-Induced Obesity (DIO Model) and Diabetes Modeling

Woodland offers several options for DIO studies under strict IACUC-approved protocols

  • C57Bl/6 mice on HFD (Taconic DIO model)

  • ob/ob or db/db mouse studies

  • Zucker Diabetic Fatty Rat (ZDF) are obese, hyperphagic hyperglycemic and insulin resistant and thus useful for diabetes studies, whereas Zucker Fatty Rats (ZF) are similar but not hyperglycemic and more frequently used in obesity research. Zucker rats have a mutation in the leptin receptor similar to db/db mice.

  • BW gain / loss acute or chronic

  • > 20% BW decreases may be observed

  • Glucose Tolerance Testing, oral (OGTT) or intraperitoneal (IPGTT) studies 

  • 10-14 day studies with dramatic effects

  • Hi-fat fed Sprague-Dawley Rats also available

  • Woodland is collaborating with Taconic to advance this model for liver fibrosis and NASH studies

  • Representative protocol and datasets available for review


Woodland Biosciences is a premier strategic partner to drug developers with liver-directed therapies, including NAFLD, NASH, fibrosis, and hepatocellular carcinoma (HCC) and pancreatic cancers.

Metabolic diseases: Diet-Induced Obesity (DIO), Fatty Liver Disease (NAFLD) and NASH with Fibrosis.

Mouse NASH model: Following industry standard protocols, Woodland establishes liver disease in male and female mice with an acute chemical insult in neonatal pups followed by chronic insult to the liver by adding a high fat, high fructose diet (HFD) selected to give enhanced steatosis and inflammation.  Ultimately, stellate cell activation to a myofibroblast phenotype and immune infiltration leads to inflammation, cellular damage, tissue injury and repair, resulting in the collagen deposition characteristic of NASH. ​Our model has been optimized to evaluate drug targets impinging on fat deposition (steatosis) , inflammation and directly on fibrosis and its reversal.  Scoring is available by DVM pathologist or by digital analysis (partnered with Fimmic Oy).​

Hallmarks of the model are:
 

  • HYPERGLYCEMIA

  • STEATOSIS

  • INFLAMMATION

  • BALLOONING DEGENERATION 

  • MILD TO MODERATE FIBROSIS

A prototype accelerated, metabolically-driven NASH model to cut the timeline in half is currently being evaluated at Woodland.  See R&D section.

A further hallmark of the Woodland model is the development of hyperproliferative disease presenting as precancerous lesions and HCC. As liver cancer is one of the more lethal sequelae of liver disease, we believe this is an important scoring parameter in studies. Several drugs that have worked to reduce fibrosis also reduce the number and size of these lesions which may have significant clinical implications. Data below was presented at national meetings in 2016 & 2017 (posters available by request).

Liver fibrosis and cirrhosis is characterized by hepatocyte death and a hyperproliferative response in a normally quiescent organ. DNA synthesis and cell division in an organ whose function is detoxification of xenobiotics sets up a perfect storm for the formation of liver cancer (HCC). Drugs that show efficacy in reducing fibrosis and other NASH parameters have been shown to significantly reduce these precancerous hyperproliferative lesions in our  Male NASH model. Excerpts from our posters with Catabasis (left) and Zafgen (right) are shown below.

Woodland's Ongoing Research & Development
 

Woodland is working to exacerbate fibrotic disease  with different physiologically-relevant liver insults including gut-liver axis agents and alcohol. 

Insulin sensitizers work effectively to lower plasma glucose with beneficial effects on liver fibrosis. Please inquire if you have questions, or would like to see 2017 AASLD poster with Zafgen.

Woodland has introduced chemical insult liver fibrosis models to our expanding liver disease portfolio.  We routinely run the carbon tetrachloride (CCl4) liver fibrosis model.

 

In addition, we also have a thioacetamide (TAA) chemical insult model in both mouse and rats following the protocols proposed by Dr. S. Friedman in his landmark 2015 'SOP' paper.  Please schedule a call for more information.

Fibrosis images - NASH and chemical insult

Fibrosis modeling in mice is challenging, the standard NASH metabolically-driven model with all features of classic NASH - steatosis, inflammation, ballooning degeneration and achieving significant fibrosis is perhaps the most challenging.

We continue to push the frontiers in liver fibrosis and disease modeling in our R&D section of the website.

Representative images from our liver fibrosis work are shown below for metabolically-driven, classic NASH; Carbon Tetrachloride (CCl4)-induced lesions; and a thioacetamide  (TAA) treated rat liver. Shown below are FFPE slides stained with picrosirius red (PSR) that stains collagen in tissue. Click the image to see description.

Left to right from left: Male NASH enhanced, Female NASH (enhanced), Male NASH standard, Rat TAA at 8 wks, mouse CCl4 at 2 wks and 6 wks.

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©2019 by Woodland Biosciences.

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