Fight Aging!

The mammalian liver is an odd organ, all things told. It has the greatest natural capacity for regeneration among our internal organs, which makes it a prime target for research into regenerative medicine. On the one hand we want to know exactly why the liver has this ability to regrow large sections of lost tissue in mammals, something that none of our other organs can manage, while on the other hand the fact that it can do this suggests that achieving greater results with either stem cell treatments or growing an entire new liver from a patient's own cells should be easier than is the case for other organs. However, the more time that researchers spend digging into the mechanisms of liver regrowth, the more they find that the biological details are quite different from those of other organs. Thus in fact the liver might not be the best place to look for ways to create a general platform for enhanced regeneration throughout the body. It is entirely possible that ways to manipulate liver biochemistry to enhance regeneration may have only limited application elsewhere.

This news of recent research well illustrates these points. In comparison to other organs, the liver may be far more reliant on a widespread as-needed transformation of normal cells, rather than a small population of empowered stem cells, when it comes to regrowth and regeneration. This has echoes in it of what is known of the way in which lower animals such as salamanders regenerate organs and limbs, which makes sense in this context:

A new model of liver regeneration: Switch causes mature liver cells to revert back to stem cell-like state

Switching off the Hippo-signaling pathway in mature liver cells generates very high rates of dedifferentiation. This means the cells turn back the clock to become stem-cell like again, thus allowing them to give rise to functional progenitor cells that can regenerate a diseased liver. The liver has been a model of regeneration for decades, and it's well known that mature liver cells can duplicate in response to injury. Even if three-quarters of a liver is surgically removed, duplication alone could return the organ to its normal functioning mass. This new research indicates that there is a second mode of regeneration that may be repairing less radical, but more constant liver damage, and chips away at a long-held theory that there's a pool of stem cells in the liver waiting to be activated.

"I think this study highlights the tremendous plasticity of mature liver cells. It's not that you have a very small population of cells that can be recruited to an injury; almost 80 percent of hepatocytes [liver cells] can undergo this cell fate change. "I think that maybe it is something that people have overlooked because the field has been so stem cell centric. But I think the bottom line is that the cells that we have in our body are plastic, and understanding pathways that underlie that plasticity could be another way of potentially manipulating regeneration or expanding some kind of cell type for regenerative medicine."

Hippo Pathway Activity Influences Liver Cell Fate

The Hippo-signaling pathway is an important regulator of cellular proliferation and organ size. However, little is known about the role of this cascade in the control of cell fate. [We] demonstrate that Hippo pathway activity is essential for the maintenance of the differentiated hepatocyte state. Remarkably, acute inactivation of Hippo pathway signaling in vivo is sufficient to dedifferentiate, at very high efficiencies, adult hepatocytes into cells bearing progenitor characteristics. These hepatocyte-derived progenitor cells demonstrate self-renewal and engraftment capacity at the single-cell level.

As the researchers note, this is a promising set of results from the point of view of generating supplies of liver cells for research and regenerative therapies - which is no small thing. It is probably of little application for anything other than liver tissue, however.