Liver disease represents a significant public health concern and was diagnosed in roughly 4.5 million adults in the United States in 2018. The liver is an important organ responsible for a multitude of vital functions in the human body. When the liver fails to function appropriately due to damage, serious consequences may emerge, ranging from life-threatening internal bleeding to significant metabolic and neurologic disturbances. Although the liver is an organ with significant regenerative capacity, long-standing conditions such as chronic alcoholism and hepatitis C can damage the liver beyond its ability to repair itself adequately. In these instances, a transplant is often the only viable option for patient survival. However, transplants come with several drawbacks such as a shortage of available donor organs, high operative risk for the donor, the long-term requirement of immunosuppression for the recipient, and financial cost. As a result, alternative therapies are being investigated.
In cell biology, the term ‘progenitor cell’ is used to describe a cell type that, under the right set of circumstances, can differentiate into a specific kind of ‘target cell’ such as a mature liver cell. In a novel animal study published in 2016, investigators assessed whether mature liver cells could undergo redifferentiation to progenitor-type cells under the influence of certain small molecules. Mature liver cells were isolated from rats and exposed to a small molecule combination referred to as YAC. These ‘YAC-induced’ proliferative cells expanded in-vitro and possessed high levels of certain liver progenitor cell markers after 2-week culture with YAC. These cells, coined “chemically-induced liver progenitor (CLiP) cells,” demonstrated the capacity to differentiate into adult liver cells and biliary cells. The rat CLiPs were transplanted into mice with chronic liver injury and shown to replace damaged liver tissue with up to 90% efficiency.
The results of a more recent study published in 2019 demonstrated that human infant hepatocytes could be reprogrammed into ‘progenitor-like cells’ using similar methods to those illustrated above. These cells had a robust ability to replace injured mouse hepatocytes and demonstrated the capacity to develop mature liver cells. The cells also possessed cytochrome enzymatic activity similar to that seen in primary human liver cells. These types of enzymes play an essential role in drug metabolism.
Although there are still significant limitations in our understanding of the mechanisms underlying the observations above, potential future applications are extensive. They include a strategy to support patients on a transplant waiting list and a new way to study chemical pathways involved with drug metabolism. These results help to expand our knowledge of cellular reprogramming and guide future research in this exciting field.