Peng et al. Hepatology.
The liver is the most regenerative solid organ in the body. One can resect 2/3 of the liver and it will still regenerate back to normal size. There have been several experimental studies in animals where induction of liver injury is treated by administration of bone marrow stem cells. A video describing this may be seen at this link http://www.youtube.com/watch?v=XGdehdRApb0. Previous use of bone marrow cells in patients with liver failure has been described in a Japanese publication that is presented in this video http://www.youtube.com/watch?v=DdH6Mm4w98I.
A recent study Peng et al. Autologous bone mesenchymal stem cell transplantation in liver failure patients caused by hepatitis B: Short-term and long-term outcomes. Hepatology. 2011 May 23 from the 3rd Affiliated Hospital of Sun Yat-sen University, in GuangZhou, China reported outcomes of 53 patients with hepatitis B induced liver failure treated with 120 ml of their own bone marrow stem cells infused via the hepatic artery. These patients were compared to 105 control patients that were matched for age, gender, and liver enzymes. Additionally, the functional index of liver failure, the Model for End-Stage Liver Disease (MELD) score, was matched between the treated and control groups.
Bone marrow stem cells were isolated without complications. The cells were administered as a slow infusion into the hepatic artery. Given that hepatitis is associated with an increase in hepatic cancer, one of the concerns of bone marrow stem cell administration into this patient population is the theoretical possibility of accelerating tumor formation. This appeared not to be the case. Specificallyt, follow-up at 192 weeks post treatment revealed no differences in incidence of hepatocellular carcinoma (HCC) or mortality between the two groups. Additionally, there were no significant differences in the incidence of HCC or mortality between patients with and without cirrhosis in the transplantation group. In terms of efficacy, it appeared that 2 to 3 weeks after administration of bone marrow stem cells, the levels of ALB, TBIL, PT and the MELD score of patients who received stem cells were significantly improved as compared to control patients. Improvements where maintained in the majority of patients.
These data support the possibility of using autologous stem cells in the treatment of liver failure. One possible new and less invasive method would be to mobilize the existing stem cells of the patient by administering drugs such as G-CSF (Neupogen) that trigger entry of bone marrow stem cells into circulation. The therapeutic activity of stem cell mobilization was demonstrated by Zhang et al. Granulocyte colony-stimulating factor treatment ameliorates liver injury and improves survival in rats with d-galactosamine-induced acute liver failure. Toxicol Lett. 2011 Apr 27 who demonstrated that 5 day administration of G-CSF had therapeutic effects in the d-galactosamine-stimulated liver failure model.
Bone Marrow Stem Cells Successful For Liver Failure Caused by Hepatitis B
Forcing Stem Cells into Circulation Results in Protection from Liver Failure in Animals
Zhang et al. Toxicol Lett.
While previous studies showed that administration of bone marrow cells are capable of repairing livers in animal and human studies, relatively little work has been performed to augment existing means by which the body uses its own stem cells to heal the liver. Specifically, it has been demonstrated that in liver failure bone marrow stem cells exit the bone marrow and home to the damaged liver. While conventional approaches include performing a bone marrow aspiration and mechanically placing the bone marrow into the liver, usually vial the hepatic artery, an alternative would be administration of a chemical that “instructs” the bone marrow stem cells to exit the bone marrow and go into systemic circulation. The other approach would be to augment the chemical signals that the injured liver produces to attract stem cells. This approach is currently pursued in other indications by the company Juventas. Stromal Derived Factor (SDF)-1 is produced by injured tissues and induces migration of bone marrow stem cells. The genetic administration of SDF-1 into already injured tissues causes an increase in stem cell trafficking and has been demonstrated to augment existing regenerative mechanisms.
A recent study (Zhang et al. Granulocyte colony-stimulating factor treatment ameliorates liver injury and improves survival in rats with d-galactosamine-induced acute liver failure. Toxicol Lett. 2011 Apr 27) from the First Affiliated Hospital, School of Medicine, of the Xi’an Jiaotong University demonstrated that administration of the stem cell mobilizer G-CSF into rats with chemically induced liver failure results in prolonged survival and the appearance of liver regeneration.
The investigators administered a single dose of d-galactosamine (d-GalN, 1.4g/kg) to induce ALF. After 2h, the rats were randomized to receive G-CSF (50μg/kg/day), or saline vehicle injection for 5 days. In the liver failure model, 5-day survival after d-GalN injection was 33.3% (10/30), while G-CSF administration following d-GalN resulted in 53.3% (16/30) survival (p=0.027). G-CSF treated rats had lower ALT level and less hepatic injury compared with saline vehicle rats. The increases of CD34+ cells in bone marrow and liver tissue and Ki-67+ cells in liver tissue in G-CSF treated rats were higher than those in saline rats.
These data suggest the possibility that stem cell therapy using chemicals that mobilize endogenous stem cells may be useful in the treatment of liver failure. It remains to be seen whether other chemicals associated with mobilization may cause improved outcome. For example, in addition to G-CSF, agents such as M-CSF, GM-CSF, parathyroid hormone, and the CXCR4 antagonist Mozibile are all capable of inducing mobilization of different types of stem cells.
Injured Liver Calls in Bone Marrow For Help?
Li et al. Cells Tissues Organs
It is known that administration of bone marrow cells into patients with liver failure has the ability to improve enzyme function and overall health http://www.youtube.com/watch?v=DdH6Mm4w98I. Additionally, numerous animal models have demonstrated that injection of various types of stem cells can result in regeneration of injured liver tissue. For example, Manuelpillai et al demonstrated that injection of human mesenchymal stem cells derived from the amnionic membrane into immune competent mice whose livers were damaged by carbon tetrachloride results in reduction in liver injury http://www.ncbi.nlm.nih.gov/pubmed/20447339. Even more interesting, administration of compounds that “instruct” bone marrow cells to enter circulation such as G-CSF, have been demonstrated to improve liver function and actually prevent mortality after liver injury http://www.ncbi.nlm.nih.gov/pubmed/20881764. This is relevant because G-CSF is a medication that is FDA approved and possesses a favorable safety profile.
One of the main scientific questions in the area of liver failure is whether the liver is actually “calling in” bone marrow stem cells to try to heal it after liver damage, or whether the therapeutic effects of stem cells in liver failure are an epiphenomena. In situations of cardiac damage after an acute myocardial infarction it has been demonstrated that the injured tissue causes upregulation of the protein SDF-1, which recruits bone marrow stem cells into the heart in order to promote healing. Whether similar mechanisms are at play in liver injury is not known. Part of the puzzle has to do with the fact that liver injury is a more chronic process than heart attacks and therefore recruitment of stem cells may be occurring at a much lower level. Alternatively, it is also known that chronic inflammatory processes actually suppress stem cell activity. So it may be that in chronic liver failure the stem cells are actually inhibited from possessing regenerative function.
This question was addressed in a recent study in which the gene expression profile of bone marrow cells was examined in animals with liver failure induced by administration of the hepatotoxin D-galactosamine to rats. To assess gene expression the Affymetrix GeneChip Rat Genome 230 2.0 Array was used, which quantifies gene expression of every gene in the rat genome. The scientists found that more than 87.7% of the genes/probe sets that were upregulated more than 2-fold in the bone marrow cells of rats with liver failure were also expressed by the liver cells, including 12 genes involved in liver development, early hepatocyte differentiation and hepatocyte metabolism. The concurrent upregulation of these genes was verified by the technique of reverse transcriptase polymerase chain reaction (RT-PCR).
The scientists also found that 940 genes were expressed in both the bone marrow cells of rats with liver failure and the hepatocytes of rats with liver failure but not in control cells. Specifically, many of the genes that were uprgulated in both the bone marrow and the liver seemed to be involved in regeneration of damaged tissue.
These data support the concept that the bone marrow stem cells can respond in similar ways to liver cells to injury. The hypothesis has been proposed by the authors that the bone marrow acts as a reservoir for the stem cells that are capable of regenerating liver. The mass amount of data in this publication is very interesting and requires detailed analysis to make sense of.
