Promoting in vitro propagation of primary human hepatocytes as organoids using cues from natural liver regeneration
Description: Liver disease is a severe and accelerating global health crisis and the only cure is organ transplantation. Novel regenerative medicine approaches show promise, but require unattainably large numbers of hepatocytes, the main functional cells of the liver. Despite their unique ability to regenerate in vivo, hepatocytes cannot grow in standard culture formats in vitro. However, our lab recently succeeded in growing these cells transiently in vitro as 3D mini-organs, called organoids. Remarkably, when implanted into a mouse with liver disease, these human hepatocyte organoids compensate for liver functions. This is a critical step in creating a reliable hepatocyte source for regenerative medicine. Despite progress, hepatocytes cannot grow long-term in vitro as organoids, which is essential for clinical translation. Recent studies, including my PhD research, indicate that supportive cells, such as vasculature, guide hepatocytes during development and renewal. We hypothesize that cues from supportive cells drive regeneration and can promote long-term hepatocyte growth as organoids. To test this hypothesis, we will create a high-resolution gene expression atlas of liver regeneration and identify restorative signals. We will then evaluate the extent to which these signals promote human hepatocyte organoid growth long-term. Lastly, we will evaluate and refine the ability of these cells to engraft in vivo and compensate for liver function. This proposal has basic and translational impacts, including improving our understanding of in vivo regeneration and the signals that guide liver reconstruction after injury. Harnessing this natural regenerative ability will enable the reliable growth of hepatocytes for basic liver biology, regenerative medicine, and pharmacological screening. Uncovering restorative cues in the liver can also enable the recapitulation of this ability in non-regenerating organs, such as the brain and heart, to treat neurodegenerative and cardiac diseases.
Amount: CA$22,500
Funding type: fellowship
Funder scheme: CIHR Fellowship
Start date: 2023-04-01
End date: 2023-10-01
Investigator: Jeremy Lotto
Institution: University of Washington (Seattle)
Subfield: Hepatology
Field: Medicine
Domain: Health Sciences
Funded outputs count: 0
Funder award ID: 187829_1
OpenAlex ID: G7211513128