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How liver stem cells help in liver regeneration

Under physiological conditions, cell turnover in the liver is very less, about one in 300 hepatocytes divide to maintain the liver mass. However, in response to simple injury such as partial hepatectomy, repair is mediated by proliferation of endogenous hepatocytes without need for any adjunctive repair pathways. But hepatocyte replication is compromised in conditions of chronic liver injury and overwhelming acute injury. This is when endogenous liver stem cells known as hepatic progenitor or oval cells are activated and contribute to the repair process.

The concept of a liver stem cell or progenitor cell has not been widely accepted until the last decade. This is because there are numerous studies which clearly show that pre-existing fully differentiated liver cells, the hepatocytes responsible for its metabolic function and cholangiocytes (bile duct cells) are quite capable of replacing liver tissue lost as a consequence of liver injury.

Recent studies investigating liver regeneration report the proliferation of a subpopulation of small, oval‐shaped cells, which are first observed in the portal triad, adjacent to the terminal ducts. These cells, termed liver progenitor oval cells (LPCs) are shown to participate in liver regeneration in a variety of rodent models of chronic liver damage.

The LPC is located periportally and it is a rare cell in normal liver occurring at a frequency of 1 in every 10,000 liver cells. They express markers common to hepatocytes and cholangiocytes suggesting they are a common precursor of both liver cell lineages. Supporting evidence for liver stem cells has also come from cell tracing studies which show transdifferentiation of bone marrow cells into hepatocytes in both human and animal models.

Interest in liver stem cells and progenitor cells has been further fuelled by the need for alternatives to liver organ transplant as the method of choice for treating end-stage liver disease and liver failure.

There exists a wide donor-recipient gap in liver organ donations. This is mainly because of poor donation rates coupled with the current global rise of liver diseases. In this regard, establishing the utility of liver stem cell transplant as an alternative to donor liver through liver stem cells and progenitor cells supports a significant role of liver stem cells in liver organ transplantation.

Another important issue is the link between LPCs and hepatocellular carcinoma (HCC). Their numbers correlate with the severity of liver disease. It is well known fact now that alcoholic liver disease and hepatitis C virus predispose patients to the development of HCC. LPCs have been transformed into tumorigenic cells in vitro by forced expression of oncogenes. Therefore it has been suggested that they may be precursors of HCC.

However, to utilize LPCs for cell therapy, maintaining and differentiating them in culture is important. Then, it is essential to know how to store them, thaw and grow them as required. Since they are a potential source of HCC, research is focused on understanding the mechanisms which underlie their transformation to cancer.

In order to treat liver lesions, much research has been performed on stem cells, especially mesenchymal stem cells (MSCs), to promote liver regeneration after hepatic injury.

MSCs have the ability to differentiate into hepatocytes and also to induce immunomodulatory and anti-inflammatory responses. MSCs can be obtained from multiple sources in the body, including bone marrow, umbilical cord blood, and adipose tissue.

Many studies have used MSCs to treat cirrhosis or to improve it, implying trans-differentiation into functional hepatocytes, and MSCs have also been shown to downregulate pro-inflammatory and fibrogenic cytokine activity, to stimulate hepatocellular proliferation, to promote collagen degradation by matrix metalloproteinases, and to reduce hepatocyte cell death and therefore increase their proliferation.

Internationally, research groups are making significant contributions in this upcoming area.  In the USA, the University of Washington, Seattle, the National Institute of Health, Maryland, and the Pasteur Institute in Paris are doing pioneering work. Human LPCs studies are being undertaken  across several UK laboratories. New strategies for liver regeneration will include progress made in tissue engineering and the use of 3D scaffolds.