Role of Haematopoietic Stem Cells in Liver Repair - Research Paper Example

Role of Haematopoietic Stem Cells in Liver Repair In order to explore what part the haematopoietic stem cells play in repairing the liver we must first investigate through the terms and the very basis of our own research, which leads us to the problems generally faced regarding livers; liver diseases drop a heavy burden on the humans. Liver is an important metabolic organ that regulates the supply of energy, secretes several important and essential compounds and clears the substance by recycling, excreting and by inactivation. The loss of the liver activity results in the metabolic instability and destruction of the essential functions of the body. If the liver tissues are not repaired or replaced properly then a number of complications occurs, the most important of them is the uncontrolled bleeding of the organs. Approximately 17% of the total population in United Kingdom are affected by the liver diseases. Among them Cirrhosis is an important cause of death of the people. Cirrhosis is a chronic liver disease, the end stage of the long term Liver damage. Cirrhosis replaces the liver tissues by the scar tissues. Other liver diseases include Chronic Viral Hepatitis, Liver Cirrhosis due to alcohol abuse, HCV (Hepatitis-C Virus) infection, HCC (Hepatocellular Carcinoma), Hepatic Fibrosis as a result of some auto-immune disease or HBV (Hepatitis-B Virus) infection or liver fibrosis as a result of drug abuse, metal poisoning or numerous other Hepatic disorders that could cause the improper function, damage or even failure of the concerned organ. The point being that the general results of these disorders are considered very drastic in nature; off which, the disruption of the acid – base equilibrium and the uncontrolled bleeding in multiple organs including the kidneys and the brain are more than enough to be mentioned, whereas the treatment or the cure simply does not exist at a level to be considered favourable by most, and what therapeutic option are we left with (if there ever was any option) is simply the complete transplant of the hepatic organ, which in turn gives rise to complexities upon complexities including the painstaking search for the perfect donor to provide a liver (which I assure; is very hard to find) and the side effects the patient would have to live with, for the rest of his/ her life.(Habib 2007). What our bodies’ response, with regards to some of the many mentioned disorders that totally disrupt the Hepatic function, is the restoration of the quiescent liver cells thus enabling them to jump back into the cell cycle and divide rapidly and efficiently to cope with the injury. Regenerative medicine using the stem cell therapies is an attractive therapy for the patients suffering from the severe liver failures. This regenerative medicine approach is of three types. The first type is the use of the cells that are having the plasticity (i.e) the ability to produce different types of cells from the stem cell. The second technique is using the tissue engineering principle. The third approach is the use of the bio artificial devices. Among the three approaches, the use of the cell therapy using the autologous, bone marrow cells is the easier technique to adopt than the other approaches. However, cell proliferation does not take place in a regular manner in an Adult Liver organ, and yet the very initial defence system devised by nature in our Hepatic organ against any injury is the self- restoring of Liver mass through cell proliferation, thus indicating the nature’s reserve of hepatocytes at the ready disposal of the liver, when in need. While cell proliferation starts to produce liver mass rapidly, Hepatic Progenitor Cells (HPCs) start to act and assist in producing hepatocytes along with the earlier mentioned differentiation of cells for liver mass restoration. The use of stem cells for the tissue regenerative medicine is becoming popular because of many reasons; ease of harvest, proliferation capacity, efficiency in in-vitro transfection and the potential use of the autologous cells. (Sokal et. al 2007). The stem cells from the extra hepatic and the intra hepatic sources are found to have the generating capacity of the hepatocyte like cell lineages. These sources are now characterized and found to have increasing opportunity in the liver cell therapy. Instead of going for the whole organ transplantation, the liver cell transplantation is found to have greater performance level at in vitro levels and in autologous transplant procedures.(Sokal et. al 2007). The plasticity of the stem cells in the bone marrow to differentiate into other cell lineages is widely reported. The currently modelled technique of liver cell transplantation has three tiers of cell replacement. Mature hepatocytes and the cholangiocytes responses to the normal cell number turn over and mild injuries. (Habib 2007). The second tier consists of an intra organ stem-cell compartment, which on activation leads to the formation of the hepatocytes. The third tier consists of the stem cells from the circulation. The random distribution of this stem cell to the sites of injury can cure the damage. Adult haematopoietic Stem cells for hepatocyte regeneration: Bone marrow contains many cell types such as stroma, vascular cells, adipocytes, osteoblasts, mesenchymal and haematopoietic stem cells. Thus bone marrow cells are found to have the ability to produce different cell populations from them. Though at the beginning it was believed that they contained only the bone marrow regenerative cells, the recent studies have showed that they are multi-potent cells. The haematopoietic stem cells are responsible for the formation of the blood and the immune system through out the life. The adult bone marrow cells are reported to produce the different hepatic epithelial cell types, including the oval cells, duct epithelium and the hepatocytes. (Habib 2007). Of the three types of cell, the haematopoietic stem cells (HSC) are an important source of liver epithelial cell replacement. These HSC’s are found have greater importance for the chronic injury, these cells require cytokines and the growth factors such as hepatocyte growth factor, transforming growth factor and epidermal growth factor for their in vitro differentiation and growth.(Lanza 2006). There are five Types of Haematopoietic Stem Cell Transplants. They are syngenic, autologous, allogeneic, peripheral stem cell and Cord Blood. Syngenic means the used of the bone marrow from the identical twin. Allogenic refers to the acceptance of the bone marrow from a donor who has similar genotyping as that of the patient. Autologous means the patients own bone marrow is harvested, treated and stored and re-infused. In the peripheral stem cell type, the stem cells are collected from the blood and not from the bone marrow. The stem cells can also be collected from the umbilical cord blood cells. This cord blood can be received from their sibling or the unrelated donors. (Bethesda 2009). How stem cell is involved in Liver repair? According to Habib, the HSC enters the peripheral blood or the lymph by the egression from the organ/tissue. After a time period these cells are attracted by the chemo-attracting gradient and moves into the repairing place. The HSC’s gets attached to the endothelium cells and then sequentially penetrates the vessel wall. These cells then adopt certain mechanism to protect themselves from the apoptosis and an environmental niche is created. With the help of this environmental niche they expand and regenerate the damaged tissues. This haematopoietic stem cell therapy is now widely used for the treatment of the liver diseases. (Greer 2006). Animal studies followed by the human studies were performed with greater efficiency. The studies of Petersen etal showed that the bone marrow stem cells can be used as a potential source for the formation of the oval cells. Similarly the stromal cells that express the features of the cytokeratin-8, vimentin, osteospondin and alpha muscle actin are present in the epithelium, mesenchyme and the vascular smooth muscles respectively. These help in the long term proliferation of the HSC. The Oncostatin M was found to induce the hepatic maturation. All the above statistics were given based on the studies. (Lanza 2006). The use of bone marrow stem cells was tested by introducing a liver injury with the 2-AAF-CCL4 drug on the test animal. Then cross sex-bone marrow transplantation was done .The regenerated hepatic cells were found to have the bone marrow origin which was confirmed by the use of the markers for the Y chromosome i.e. dipeptidyl peptidase IV and the L21-6 antigen, where the L21-6 antigen is used to identify the donor- derived cells. They used the FISH technique for the analysis of the Y-chromosome and to observe the rare cell event. (Katalin, 2007). All the animal studies done with the immunodeficient mouse models having the liver damage have indicated that the adult haematopoietic stem cells can be used in the regenerative medicine. These adult haematopoietic stem cells secretes some biological factors, which suppresses the formation of the scar tissues and thus inhibits the apoptosis and enhances the recruitment, retention, mitosis and enhances the angiogenesis. (Zhau 2009). The human studies are also conducted on the other hand. The autologous CD34+ cells were injected into the patients suffering from the liver failure and the result was a definite decrease in the serum bilirubin. Although the studies show a promising result for the use of the bone marrow stem cells is still not widely accepted and proved. The main reason is the variation in the range of the results among the scientists.(Katalin 2007). The acute liver injury is another area where liver repair mechanism is used. Here the animals were pretreated with the retrosine to inhibit the replication of the nature to inhibit the replication of the native hepatocytes. When these animals were subjected to partial hepactomy, under the no cell fusion or hepatocyte or bone marrow cell fusion, it was found that the bone marrow cell fusion was found to be higher than the other two types. This method of demonstration of the bone marrow derived cells and their function in the liver is called as analbuminemic method. (Gilchrist 2010). The correction of the inborn errors was tried with the plastic bone marrow stem cells. The bone marrow transplantation for a lethal hepatic disorder correction was done to look for the rate of success in the animal model. Here the donor chosen was synergic; it thus eliminates the host graft disease and the immuno suppression level. Here even a low percentage of the engraftment efficiency is enough for the scientist to have a greater success in the near future. The rodent models which have the similar liver structure, function was chosen for the study. When a new graft is introduced into the model’s body, at first the model will consider it as a foreign body and thus try to eliminate it, so the immune response to the bone marrow fusion was managed by the immuno suppression method using the cyclosporine. (Gilchrist 2010). Isolation of the haematopoietic stem cells: The CD34 protein was widely used as the marker for the positive selection of the human haematopoietic stem and the progenitor cells. Recently it was proved that CD34 protein expression can be turned on and off according to the needs. It was shown from the studies that CD34+ highly purified cells produced CD34- cells and when these cells were re-isolated, it was found that they were able to produce CD34+ cells. (Motonari, 2009).The CD34+ protein expression at the cell surface and at the mRNA level can be turned on and off according to the needs. Thus CD34 protein expression hypothesis was wrong. Recent studies have also showed that the Aldehyde dehydrogenase enzyme (ALDH) was found to have greater correlation with the in vivo stem cell activity.(Zhou, 2009). The progenitor function and the ability of the cells in reconstituting were found to be high when the ALDH concentration was high in the cells. Similarly the hepatocyte growth factor, which is produced in the marrow stromal cells, suggests that they have some role in the maintenance of the HSC. (Okita 2004).The HGF is also found have some role in the tissue repair mechanism, where the concentration of the HGF was found to be higher for the up regulation and lower for the down regulation under the controlled patterns. The Kupffer cells were found to up regulate the HGF mRNA. One of the important signals that the stem cells receive after an injury is the signal for the induction of the stem cells for migration into the damaged tissue and for the repair and the survival of the stem cells at the damaged site.(Zhou 2009). Signals involved in the bone marrow mobilization: Strolam derived factor–1 a chemokine is involved in the trafficking of the stem cells, the fatal stem cells and the adult stem cells, to the correct destination. (Gilchrist 2010) Importance of the adult stem cell therapy in chronic liver disease: The hepatocyte proliferation,increasing the number of the epithelial cells,increasing the alpha- feto protein expression are the requirements of a successful adult stem cell therapy, this was successfully achieved by the use of the autologous cell infusion technique. The mobilization of the CD133+ was reported in all the transplantations, thus proving the efficiency of the direct cell infusion into the vein. The direct cell infusion through the vein helps in the homing of the stem cells to the liver directly and makes the cells to proliferate in the liver normally and this technique does not require any injury at the targeted site. The chronic liver injury, cirrhosis can also be cured using the adult stem cells from the bone marrow. The method cell infusion with the granulocyte colony stimulating factor provided a greater improvement in the serum albumin and the prothrombin level in both the control and the test groups. However the serum albumin concentration was greater in the test group, thus providing a mark able achievement in the adult stem cell therapy using the bone marrow stem cells. (Zhao 2009, Gilchrist 2010). Future challenges: The stem cell therapies hold a great promise in cell repair, restore and regenerate the damaged liver. The stem cell has the greater potential to perform more efficiently than the current pharmacological devices or the mechanical devices. The first challenge that is considered for the stem cell therapy is the safety level. The in vitro and in vivo assays always have the question of safety. The second challenge is that the in vivo functionality determination in small animal models combining the metabolic disorders and then screening for the cell function. Large animal models always have the safety issues and functionality issues. So a standard and acceptable immuno suppression program and a cell injection program must be properly designed. The another challenge faced by the Hematopoietic stem cell mediated liver repair is the difficulty in bringing out this regenerative medicine from the laboratory scale level to the pilot level and then to the patient care. A lot of intensive effort is to be dropped here for the success. The methods that are currently used for the treatment had no controls for the studies; more over the pathophysiological studies have showed that the bone marrow derived hepatocytes are possible only for the specific models. What ever is the challenge the biological features of the stem cells have lots of hope for a better world in the future clinical applications. (Gilchrist 2010). References: Bethesda 2009, Chapter 5.Hematopoietic Stem Cells, National Institutes of Health, U.S. Department of Health and Human Services, last accessed on April 16, 2010, http://stemcells.nih.gov/info/scireport/chapter5.asp,. Gilchrist, E.S and Plevris, J.N 2010, Bone Marrow-Derived Stem Cells in Liver Repair: 10 Years Down the Line, Liver Transplantation Vol.16, pp.118-129. Greer, E.V 2006, New developments in stem cell research, Nova publishers. Habib, N.A , 2007,Stem cell repair and regeneration, Volume 2, Imperial College press. Katalin, K and Zeiher, A.M 2007, Bone marrow-derived progenitors , Springer publications. Kondo, M 2009, Hematopoietic Stem Cell Biology, Springer publications. Lanza, R.P, 2006, Essentials of stem cell biology, Academic press. Okita, K 2004, Stem cell and liver regeneration, Springer publications. Zhao, Q et. al, 2009, Stem progenitor cells in liver injury repair and regeneration, Biological Cell vol. 101, pp. 557-571. Zhou, P 2009, Contribution of human hematopoietic stem cells to liver repair, Semin Immunopathology vol. 31, pp.411–419 Read More