Did you know that your liver has its own immune cells, ready to defend against infections and keep it healthy? Researchers at McEwen Stem Cell Institute have found a way to create these vital cells—called Kupffer cells (KCs)—from human pluripotent stem cells, opening doors to new treatments for liver disease.
Kupffer cells play a key role in defending the liver against infections and helping to maintain a healthy environment, making the liver more resilient to disease. They are self-renewing, long-lived, and thought to derive from progenitors produced early in fetal life.
Although the characteristics of KCs are well established, the molecular mechanisms that regulate their development and maturation from progenitor cells are poorly understood. It has proven difficult to study this, as replicating the complex liver environment for KC maturation in the lab is challenging and most of the information comes from work in experimental models.
To study this process in humans, scientists first created KC progenitor cells from human stem cells. They then transplanted these progenitors into a specialized experimental model, previously generated by their team, which was modified to provide a suitable environment for KC cell development. They achieved this by replacing the existing liver blood vessel cells in their experimental model—known as liver sinusoidal endothelial cells (LSECs)—with human LSECs generated from human stem cells. This presence of the human LSECs created the perfect environment for KCs to grow.
The team found that these lab-grown human KCs successfully integrated into the liver of pre-clinical models and that the development of the human KCs was dependent on the presence of the human LSECs. Advanced sequencing analysis confirmed that these stem cell-derived KCs had the same unique characteristics as natural KCs. The human KCs were able to perform critical functions characteristic of these cells, specifically phagocytosis, the process of engulfing dead and dying cells.
This research demonstrates the potential to generate human KCs from stem cells, opening new avenues for studying liver disease and developing regenerative treatments.
The first author of this study is Gregory Kent, a doctoral student at McEwen Stem Cell Institute in the lab of Dr. Gordon Keller.
Dr. Gordon Keller, Director of McEwen Stem Cell Institute and Senior Scientist at Princess Margaret Cancer Centre is a co-senior author of the study. Dr. Keller is a Professor in the Department of Medical Biophysics at the University of Toronto.
Dr. Blair Gage, a Scientist at the Ottawa Hospital Research Institute and Assistant Professor at the Department of Cellular and Molecular Medicine at the University of Ottawa, is a co-senior author of the study.
This work was supported by the University of Toronto’s Medicine by Design, the Canadian Institutes of Health Research, and UHN Foundation.
Dr. Gordon Keller is a founding investigator and a paid consultant for BlueRock Therapeutics LP and a paid consultant for VistaGen Therapeutics and Apiary Therapeutics.
Kent GM, Atkins MH, Lung B, Nikitina A, Fernandes IM, Kwan JJ, Andrews TS, MacParland SA, Keller GM, Gage BK. Human liver sinusoidal endothelial cells support the development of functional human pluripotent stem cell-derived Kupffer cells. Cell Rep. 2024 Aug 27;43(8):114629. doi: 10.1016/j.celrep.2024.114629. Epub 2024 Aug 14.