The Advantages of ExVive 3D Bioprinted Liver Tissue in Capturing the Complex Cellular Events of Monocrotaline-induced Liver Injury
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Monocrotaline (MCT), a pyrrolizidine alkaloid causes liver injury in animals similar to that of hepatic venoocclusive disorder in humans. MCT induced liver injury occurs through a complex set of cellular insults involving multiple cell types which can ultimately lead to fibrotic changes.
In the study, which will be discussed in this webinar, we evaluated the effects of MCT in 3D-bioprinted human liver tissue comprising of primary hepatocytes, hepatic stellate cells, and endothelial cells (ExVive™ Human Liver Tissue; Organovo, San Diego CA).The bioprinted tissues were treated with MCT for fourteen days. MCT treatment led to time- and dose-dependent decreases in tissue health as measured by LDH leakage and albumin synthesis and by histopathologic changes in the tissues, as well as increases in the production of the pro-inflammatory cytokines IL-1β, IL-4, IL-8 and IL-10. Histologic assessment of formalin-fixed, paraffin-embedded tissue revealed signs of tissue damage, including dissociation of the network of hepatocytes and reduced cellularity within the tissues. Immunohistochemical analyses revealed a dose-dependent increase in CD31+ cells and a marked increase in the appearance of large, CD31+ bright cells that co-expressed smooth muscle actin (α-SMA), often forming clusters or complex multi-cellular structures.Changes in organization of CD31 expressing endothelial cells and appearance of α-SMA expressing cells are indicative of remodeling and initiation of fibrotic events.
Observations which emerged from this study capture the spectrum of changes induced by MCT ranging from reduced hepatocellular function and vascular remodeling, which may involve endothelial cell migration, organization, proliferation, apoptosis, and endothelial-to-mesenchymal transformation to early fibrotic events.
Benefits from attending this webinar:
- Gain an understanding of how 3D bioprinted tissue is a unique model in capturing complex toxicity phenotypes.
- Understand how the physiological interaction of multiple cell types is necessary to capture the cascade of events resulting in drug induced liver injury (DILI).
- Discover the utility of 3D bioprinted tissue in assessing time- and dose-dependent tissue responses, pro-inflammatory signals, and histological effects as a result of insult.
- Learn how this complex DILI triggers pro-fibrotic events in 3D bioprinted tissue.
Challenges to be addressed:
- Conventional in vitro systems fail to capture the multi-cellular mechanisms of toxicity induced by a compound such as monocrotaline.
- Histological phenotypes seen first in animal models cannot be measured in traditional in vitro models.
- Spatial and temporal mechanisms are not typically captured by current in vitro systems.
Who should attend?
Professionals which fall into any of the following categories,
Pharmaceutical Scientists, Toxicologists, Pathologists, Investigative Scientist, Disease Area Leads, Therapeutic Area Leads, Preclincal Development, Preclinical Safety, Safety Assessment, Mechanistic Safety, Veterinary Pathologist at Pharmaceutical and Biotech companies
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Dr. Umesh Hanumegowda, MVSc, PhD, DABT, is currently the Scientific Director at ViiV Healthcare in Wallingford CT. Prior to joining ViiV, Umesh was a toxicologist in Discovery Toxicology at Bristol Myers Squibb for over 12 years. His expertise is in pharmaceutical toxicology, specifically in investigative and mechanistic toxicology. The current webinar is the work done while he was at Bristol Myers Squibb.