Mature Liver Cells Seem to be Better Than Stem Cells for Liver Therapy

Japanese research team has compared the ability of liver progenitor cells (liver stem cells) and mature liver cells to effectively repopulate a damaged liver. They have concluded that mature liver cells (hepatocytes) are better than stem cells for liver repopulation.

Workers in the laboratory of Toshihiro Mitaka of the Cancer Research Institute of the Sapporo Medical University School of Medicine, Sapporo, Japan used a rat model to test these hypotheses. They injured the livers of these rats with surgery and chemicals and then used transplanted cells to repopulate these livers. Up to two weeks after transplantation, the growth rate of the stem cells was significantly higher than that of the mature liver cells, but after two weeks the majority of the stem cells died before they could confer any significant benefit on the liver. The mature cells, however, grew slower, but survived much better.

Toshihiro Mitaka made this comment: “Cell-based therapies as an alternative to liver transplantation to treat liver disease have shown promise. However, the repopulation efficiency of hepatic progenitor/stem cells and mature hepatocytes (liver cells) had not been comprehensively assessed and questions concerning the efficiency of each needed to be resolved.”

Mitaka’s team noticed that the shortage of liver cell sources and the difficulties of preserving the available liver cell sources by freezing (cryopreservation) have limited the available material, and therefore, the clinical applications of cell-based therapies for liver disease. Liver stem cells (liver progenitor cells) have been considered to be the best option to treat liver disease, since they can be expanded in culture and preserved by freezing for long periods of time.

However, once the liver progenitor cells were transplanted into the damaged livers of rats, the stem cells failed to survive terribly well. After two months, the vast majority of the transplanted stem cells had disappeared. In contrast, the mature liver cells gradually repopulated the rat livers and the even continued growing and repopulating the damaged livers for one year after transplantation.

Transplanted liver cells did not make uniform cells. Mitaka noted that “the small hepatocytes repopulated significantly less well than the larger ones. We also found that serial transplantations did not enhance nor diminish the repopulation capacity of the cells to any significant degree.”

In this paper, Mitaka and his colleagues argue that because the stem cells died much earlier than the mature hepatocytes, the stem cells were eliminated from the host livers and this reduced their potential regenerative capacity. They conclude in the paper that further “experiments are required to clarify the mechanism by which this might occur.”

My take on this is that damaged livers probably contain a respectable amount of inflammation. Therefore, they are probably a rather hostile environment for any transplanted cells. We have seen in previous posts that stem cells have a mechanism to resist stressful conditions, but also, that this pathway for resisting stress must be activated in the stem cells before they are capable of resisting stress. Therefore, I would suggest that the next experiment Mitaka and his co-workers should do, is to either precondition his stem cells with oxygen and glucose deprivation or pre-treat them with insulin-like growth factor-1 (IGF-1). Both of these treatments have been shown to activate the stress resistant pathway in stem cells transplanted into the heart. Therefore, if this pathway could be induced in liver progenitor cells, then perhaps the stem cells can be stress-adapted and tolerate the stressful conditions in the damaged livers.