The Liver Has Regenerative Capacity Hepatic Stem Cells

The liver is an organ that exhibits significant regenerative capacity; the entire organ can regrow from as little as a third of its original tissue (Vessey et al., 2001). The resting hepatocytes can undergo cell division—up to 12 to 16 divisions per cell providing the basis for this regenerative capacity (Sell, 2001). Evidence of liver stem cells capable of forming both hepatocytes and bile ducts has been demonstrated in a rodent model. Administration of a hepatotoxic agent (carbon tetrachloride) to rats pretreated with N-2-acetylaminofluorene (an agent used to block hepatocyte proliferation) creates hepatocellular injury, simultaneously blocking the normal hepatocyte proliferative response following toxic injury (Petersen et al., 1998).

Liver regeneration is believed to occur through three mechanisms: replication of existing hepatocytes, differentiation of oval cells, or hematopoietic stem cells. After a 70% hepatectomy, liver regeneration requires no more than two rounds of hepatocyte replication (Fausto, 2004). Hepatocytes have enormous proliferative potential, but there is evidence of diminished replicative activity with injury and disease. Due to the ability of liver regeneration to occur through fully differentiated hepatocytes, initial arguments were against the need or existence of a hepatic stem cell. Observations in the 1950s first indicated that another source of hepatocytes existed, termed oval cells (Farber, 1956). Oval cells refer to single cells or clusters of cells that form a ductule. They arise after toxic insult to the liver stem cells, located along the canal of Herring, and are identified based upon the expression of OV-6 (Thorgeirsson, 1996). These cells arise from an intrahepatic stem cell niche corresponding to the canals of Hering and terminal bile ductules of the adult liver.

Even though the term oval cell often is used synonymously with hepatic stem cell, whether or not they are one and the same remains in dispute. Certainly oval cells give rise to multiple cell lineages in the liver, but the oval cell may be an activated progeny of stem cells in the liver. One of the challenges facing researchers today is the lack of definitive markers of hepatic stem cells. Candidate markers include OV6, CD34, c-kit, cytoker-atins CK 7 and CK-9, chromogranin-A, and the cell adhesion molecule N-CAM (Dunsford et al., 1989; Roskams et al., 1998). Improved protocols are continuously emerging for the purification and culture of hepatic stem cells (Lazaro et al., 1998).

Some markers expressed by oval cells are also hematopoietic stem cell markers. This suggests a relationship between a liver-derived stem cell population and a circulating bone marrow-derived stem cell fraction. In fact, in sex-mismatched bone marrow transplantation experiments, oval cells and hepatocytes were found from bone marrow origin (Petersen et al., 1999). Similar findings revealed the interchangeability of tissue stem cells after transplanted bone marrow side population cells, stem cells purified on the basis of their ability to efflux Hoechst 33342 dye, could be isolated in hepatic side population cells and were recruited to repair liver damage (Wulf et al., 2003). Although there is clear evidence of cells originating from the bone marrow contributing to the formation of hepatocytes, this transformation is a rare event. Much of this work supports the phenotypic plasticity of stem cells in response to a microenvironment, but it has yet to be seen if these relatively rare events could play a noteworthy part in human liver or tissue damage repair.

Hepatic stem cells: hope for liver transplantation The immense regenerative potential of the liver makes the resident stem cells a target for cell-based therapies for a variety of liver diseases. Hepatocyte transfusion may provide a short-term solution for patients awaiting liver transplantation (Strom et al., 1997). Transfusion of cultured hepatocytes has realized some success for the treatment of metabolic conditions such as ornithine carbamoylase deficiency (Strom et al., 1997), homozygous familial hypercholesterolemia (Raper et al., 1996), and Crigler-Najjar syndrome type I (Fox et al., 1998).

Hepatic stem cells and aging Although the rate of liver regeneration declines with age, the regenerative capacity remains unchanged. The aged liver is more vulnerable to injury from toxins, viruses, and ischemia. A decline in hepatic clearance of certain drugs leads to a marked increase in the frequency of adverse drug reactions in geriatric patients. The development of cell therapy strategies for liver failure and metabolic diseases has become a necessity due to limitations on rates of regeneration in the aged population as well as shortage of donor livers. The availability of in vitro expandable progenitors would facilitate studies on cell engraftment and serve as a model for clinical applications.

Currently, cell transplantation for the treatment of liver failure is restricted to the transplantation of primary hepatocytes. Due to shortage of donor human hepato-cytes, liver stem cell research must be aimed at expanding a progenitor population in vitro. Another potential avenue for cell-based therapies includes discovering a potential functional role for bone marrow-derived cells in hepatic tissue transplant. Human fetal tissue remains a promising source of bipotential stem cells. Providing this tissue type remains accessible, these cells could be more efficient than adult hepatocytes for the repair of liver damage. At the present rate of progress, transplantation is a goal achievable within the foreseeable future.

Blood Pressure Health

Blood Pressure Health

Your heart pumps blood throughout your body using a network of tubing called arteries and capillaries which return the blood back to your heart via your veins. Blood pressure is the force of the blood pushing against the walls of your arteries as your heart beats.Learn more...

Get My Free Ebook


Post a comment