Despite the initial success of the procedure, the Edmonton protocol will not become a widely used technique until an alternative source of cells is found to supplement the limited supply of donor tissue. Currently, the use of embryonic and adult stem cells in the Edmonton protocol is a topic of much research.
Stem Cell Basics
Stem cells exhibit two important characteristics:
• They are unspecialized cells that are able to proliferate over a long period of time through cell division.
• Under special conditions, they can be induced to differentiate into specialized cells, such as the insulin-producing cells of the pancreas.
Scientists focus their study on two types of stem cells, embryonic and adult stem cells.
Embryonic stem cells , or ESC, are derived from embryos, specifically from embryos that have been fertilized in vitro . Stem cells can be taken from an embryo at four or five days of age, when the embryo is a hollow ball of cells called the blastocyst. ESC will proliferate indefinitely in defined culture, and have the capability of differentiating into any of the specialized cell types of the body. ESC will remain undifferentiated under certain culture conditions, but the formation of embryoid bodies causes spontaneous differentiation into the various cell types of the body. Scientists have developed methods to control ESC differentiation by changing the chemical composition of the medium, altering the surface of the culture dish, or modifying the cells by inserting specific genes.
In an undifferentiated state, ESC are thought to be immunologically undefined; therefore, the immune system of the recipient should hypothetically be able to program the cells to be recognized as “self” tissue, thus eliminating the need for immunosuppressive drugs.
Fig. 1 The steps of embryonic stem cell differentiation in vitro
Adult stem cells , or somatic stem cells, are undifferentiated cells found residing with differentiated cells in a mature tissue or organ. They have the capability of renewing themselves, and of differentiating into the specialized cells of that tissue or organ. Their role is to repair and maintain the tissue in which they are found. Research on adult stem cells have garnered a great deal of excitement ever since the discovery that adult stem cells are found in numerous different tissues, and that they may have the ability to differentiate into a variety of different specialized cells. This ability for adult stem cells to differentiate into cells other than those of their native tissue or organ is termed plasticity.
Fig. 2 Examples of adult stem cell plasticity
Only a small amount of adult stem cells can be found in tissues and organs, and it is believed that they remain non-dividing until triggered by some injury or distress to the tissue or organ. Current research involves developing ways to culture these stem cells and to induce differentiation to a desired phenotype. The major advantage of using adult stem cells in cell transplantation is the possibility of transplanting a patient's own cells into him/herself, circumventing the risk of immune rejection.
Current Research
Investigations of the ability of embryonic stem cells to differentiate into insulin-producing cells have been underway for several years. It has been shown that insulin expression occurs early in the differentiation of ESC. However, complete differentiation of ESC into mature pancreatic beta-cells has not been greatly successful. Pancreatic beta-cells generated in vitro exhibit a far lower insulin content than normal beta-cells.
An alternative to in vitro differentiation of ESC to islet cells is direct transplantation of undifferentiated ESC into a diabetic person. The cells would then depend on the stimuli of the surrounding tissue to trigger differentiation. This technique runs the risk of tumorigenicity since ESC's are known to proliferate in an uncontrollable manner.
Studies have shown that both hematopoietic and mesenchymal stem cells derived from bone marrow have differentiating abilities and may be manipulated into producing insulin in the pancreas. Stem cells found in the ductal structures of adult pancreases have also exhibited self-renewing and differentiating abilities in vitro. When mouse islet cells were formed from precursor pancreatic stem cells and implanted into diabetic mice, insulin independence was achieved. There has also been strong evidence for the existence of islet precursor cells in the neonatal porcine pancreas. Digestion of fetal porcine pancreas in collagenase and introduction of the digest into diabetic mice has been shown to restore normal levels of glycemia.
All of these methods represent priorities in current stem cell research and opportunities for the universal success of the Edmonton Protocol.
References:
1. http://www.insulinfree.org
2. http://stemcells.nih.gov/stemcell/whatAreStemCells.asp
3. Street, Cale N., et al (2003) Stem cell-based approaches to solving the problem of tissue supply for islet transplantation in type 1 diabetes. The International Journal of Biochemistry & Cell Biology , 36, 667-683.
4. Roche, E., et al (2003) Bio-engineering insulin-secreting cells from embryonic stem cells: a review of the progress. Medical & Biological Engineering & Computing , 41, 384-391.
5. Peck, Ammon B., Cornelius, Janet G., Schatz, Desmond, Ramiya, Vijayakumar K. (2002) Generation of islets of Langerhans from adult pancreatic stem cells. Journal of Hepatobiliary Pancreatic Surgery, 9, 704-709.
Image References:
Fig. 1: http://www4.od.nih.gov/stemcell/figure1_primer0902big.jpg
Fig. 2: http://www4.od.nih.gov/stemcell/figure3big.gif
