Stem cell research has implications for many types of therapies. The following pages will describe several of these therapeutic applications in detail.
Stem cell therapies are attractive in neurological disease, as the existing medical options are often very much suboptimal. There is some suggestion that the initial event in some of neurodegenerative diseases is a dysfunction of the neural stem cells, thus making it more amenable to stem cell treatment (Limke, 2003).
The use of stem cells in neurodegenerative disease significantly progressed with some unexpected discoveries after whole-bone-marrow transplantation in animal models. Surface markers from the donor marrow were found in non-hematopoietic cells, such as the brain. Also, in animal models with neurodegenerative disease, there was some evidence of recovery (Mezey, 2000).
Based on this finding, further trials were conducted. A retrospective study showed that bone marrow stem cells transdifferentiated into functional neurons, upon implantation into the human central nervous system (Cogle, 2004).
Furthermore, good results were demonstrated when human umbilical cord blood stem cells were placed in a suitable niche microenvironment. They successfully differentiated into neuronal stem cells, and then further differentiated into astrocytes (Hao, 2003). Astrocytes are one of the larger neuroglia cells found in nervous tissue. There are several subtypes of astrocytes, such as an Alzheimer type I and type II astrocyte, making this an important therapeutic discovery.
The old dogmatic teaching in neuroscience was that neural tissue was irreplaceable. That view is now in competition with the hypothesis that in certain areas of the human brain, the cells are being actively replaced. These brain areas include: a sublayer of the dentate gyri and the walls of the lateral ventricles that store cerebrospinal fluid in the cerebellum. The first step was to develop a protocol to isolate and expand the neural stem cells (Johansson, 1999). Then a less-invasive way to extract the neural stem cells was created: using an endoscope to extract the neural stem cells from the walls of the ventricles that could be cultured into functional neurons (Westerlund, 2003). These could then be cultured using a stem cell niche, ready for an allograft therapy (Liu, 2003).
Another sample of an interesting finding early on in stem cell research was of retinoic acid. Retinoic acid is an ingredient in medication for very severe cases of acne, and is known to be profound teratogen. Studies revealed that the retinoic acid promotes differentiation into neural cells, which has been used in some studies to procure neural stem cells from sources such as a teratocarcinoma (Saporta, 2002).
Neuronal stem cells do have obstacles. They occur only in very limited areas of the central nervous system, and are usually quiescent. Therefore, stem cell therapies for the brain will likely require some type of drug treatment as an adjuvant (Limke, 2003).
Spinal cord injury is a sudden transection or other injury of the spinal cord within the vertebral column of the spine, which usually results in focal neural deficits.
Neurotrauma is a sudden physical insult to the head, which can result in either focal or multifocal disturbances in brain function. There is an initial impact, which immediately initiates necrotic cell death of the nervous tissue. This causes a chain of further events such as ischemia and altered gene expression, which results in further apoptotic cell death in still more of the surrounding tissue (Brodhun, 2004).
Since there is an initial ischemia and injured tissue of surrounding tissue, it is hoped that infusion of stem cells soon after injury can help minimize the damage resulting from injury.
It was reported that embryonic and adult neural stem cells differentiate into astrocytic phenotypes upon grafting into injured spinal cord (Vroemen, 2003). Regarding in vitro differentiation, researchers needed to be wary of in vitro commitment being overridden by the environmental cues of the injured spinal cord (Cao, 2002).
Transplants are possible from human neural stem cells or human spinal cord tissue into the injured spinal cords of rats (Wictorin, 1992; Akesson, 2001). There were some successive reports of the recovery effects of spinal cord transplantation after injury in several human to animal models. First there was recovery noted from human umbilical cells infused into a rat spinal cord injury model, though the effects were only noted for 3 weeks following the graft (Sapporta, 2003). Next, human embryonic stem cells that were cultured into oligoprogenitors were transplanted into another rat spinal cord injury model (Saporta, 2002) with beneficial effects. Finally, human neural progenitor cells were noted to have positive effect when transplanted into a monkey spinal cord injury model (Iwanami, 2005). However, each of these studies at least one weakness: the positive identification of the grafted cells, confirmation of differentiation, evidence of integration of grafted cells into the host spinal cord, or longterm outcome data.
A more thorough study (Cummings, 2005) was recently published which sought to resolve many of these issues. The experiment began with so-called “human CNS stem cells grown as neurospheres” which were isolated from fetal brain (Tamaki, 2002). These cells were transplanted into a traumatically injured spinal cord of mice. The study confirmed that the transplanted cells survived, differentiated, and were properly grafted to existing tissue. The transplanted cells caused some recovery of spinal cord injury. If the engrafted cells were then destroyed by addition of diphtheria toxin, then the recovery effect was lost. Finally, the same study also showed that the stem cells were able to remyelinate axons in the traumatically injured spinal cord, and also to differentiate into neurons that showed microscopic evidence of synapsing in the same matter as normal neurons (Cummings, 2005).
Amyotrophic lateral sclerosis (ALS) is a fatal degenerative disease of motor neurons: corticospinal, corticobulbar and spinal. The most common motor neuron disease, it is sometimes referred to by its eponymous name of Lou Gehrig disease. Symptoms present as progressive muscle weakness and muscle wasting, then eventually results in death, usually within 2 to 5 years.
ALS has had some initial success, though many questions still remain (Silani, 2004). ALS is a rapidly fatal disease, so the move to human clinical trials was fairly quick, after animal models demonstrated that stem cells could be used for neuronal applications (Silani, 2003).
Focus has been primarily in using hematopoietic stem cells. In one encouraging experiment, seven ALS patients had a allograft of their own hematopoietic stem cells surgically implanted into the T7-T9 area of their spinal cord. Adverse effects were minimal. Three months following transplantation, in two of the seven patients, there was a minor increase in muscle strength. Four of the remaining patients had a slowing in the expected rate of decline of muscle strength (Mazzini, 2003).
Direct stem cell transplant into a small area of spinal cord is encouraging but suboptimal, as ALS has a degeneration of neurons in the brainstem and along the entire cord. However, a less invasive, more wide-ranging transplantation technique is available in the form of the cerebrospinal fluid that surrounds the cord and brain. In a study with rats paralyzed from a virus-borne motor neuropathy, stem cells injected into the cerebrospinal fluid were demonstrated to be able to invade the spinal cord (Kerr, 2003). This is helpful because the single injection of stem cells could drift up and down in the fluid surrounding the spinal cord and thus insert and heal in many different areas.
Stem cells have been used in stroke in some early human trials. In one clinical trial, neuronal cells were cultured from teratocarcinoma stem cells. The neuronal cells were then transplanted into the brain tissue of 11 stroke patients. One year after transplant, the grafted neuronal cells were still viable, as detected by a positron emission tomography (PET) scan. Fortunately, no patient developed a teratocarcinoma as a result of the transplant. In 6 of the 11 patients, symptoms were reported improved, and in 2 of those 6 the improvement was assessed as significant (Kondziolka, 2000).
One proposed mechanism of some types of cancer is the so-called “embryonal rest” theory, which hypothesizes that cancers arise from adult stem cells. Analysis of the carcinomas in several organs seems to indicate that a stem cell within the organ, usually used for tissue renewal, has gone awry and developed into a cancer. Examples of cancers that are thought to develop through the embryonal rest mechanism are Wilm's cancers of the kidney and neuroblastomas. (Sell, 2004). Skin cancer gives also gives weight to a stem cell role in cancer. Since a patient can develop a skin cancer many years after an initial exposure to a carcinogen, it is reasoned that the carcinogenic damage is done to a skin cancer stem cell, and that mutated stem cell survives and passes on the damage to later generations (Sell, 2004). Cancer of the liver has also been studied, and the liver stem cell lineage has been illustrated to cause specific cancers depending upon what stage the hepatic stem cell has stopped differentiating (Sell, 2004).
In addition to research the potential role of stem cells in causing some cancers, research is being carried out as to how stem cells are usually able to prevent uncontrolled proliferation. A clear understanding of the mechanisms by which stem cells are able to suppress their tumor capacity can lead to new ways to understanding the mechanism of cancer, thus leading to a therapy (Krtolica, 2005).
Leukemia is characterized by an uncontrolled proliferation of blood cell progenitors and their subsequent accumulation within the bone marrow and other tissues. Leukemias merits special mention as it is among the diseases with the most advanced body of evidence for stem cell therapeutics, with years of using stem cell transplants in leukemia patients.
Stem cell therapies over the years have often been allografts of bone marrow transplants from siblings having a close match. There has been a recent rise of cord blood for therapeutic treatment of leukemias, especially in the pediatric populations (Chao, 2004). New findings continue to develop in leukemia, such as the evidence that retinoid acid can be used as differentiation therapy in some forms of leukemia (Sell, 2004).
The skeletal system has the capacity to self renew after injury, within limited amounts. For example, a simple fracture of a long bone forms a callous around the broken area, reforming the shaft of the bone.
There have been several interesting case reports of replacements of large bony structures using autografts of stem cells. In these autografts, bone progenitors are first taken from the patient, grown into the three-dimensional shape of differentiated bone on a biodegradable scaffold. The resulting grown structure is than implanted into the patient. Further details on scaffolds are available in the Biodegradable scaffolds for three dimensional stem cell grafts section. In one case report, a young boy was born with only the left half of his ribcage, so a right half-ribcage was grown and reimplanted into his chest, thus protecting his heart and other organs. In a second report, a young woman ended up with a disfigured jaw following the surgical removal of a large tumor from it. Growing her stem cells onto an engineered scaffold created a replacement jaw, which worked essentially as normal upon transplantation (Mummery, 2004)
There are some technical challenges to bony three-dimensional grafts of stem cells. Firstly, they are usually only effective in people under 50 years of age. Also, an increased size of the structure can be a concern since the stem cells need to be nourished with nutrients and adequate blood supply. In large scaffolds, there is a tendency for only the stem cells near the outermost regions of the bone matrix to have sufficient nourishment (Mummery, 2004).
Osteoporosis is a decrease in bone mass. It results in increased susceptibility to fractures and is usually age-related. The condition is responsible for roughly half of all fractures in women over 50 years old. The mechanism of osteoporosis is probably diverse. However, it is known that bone is constantly being formed and reabsorbed through a cyclical process called remodeling. Certain risk factors, such as menopause and a decreased calcium intake, can cause more bone to be destroyed than be replaced, resulting in the decreased bone mass.
This remodeling concept is directly applicable to stem cell therapeutics. The stem cells could theoretically be induced to remodel lost bone, thus correcting the osteoporosis. While available clinical tools are as yet far off, there has been some initial groundwork. For example, it was shown that both the number of osteogenic stem cells and their proliferative capacity neither changes with age nor osteoporosis (Stenderup, 2001). It was then later shown that the osteoblastic differentiation capacity of human marrow stromal structures also stays constant during age and osteoporosis (Jutesen, 2002). It thus seems that the capacity of the stem cells is maintained; the therapy thus likely needs to focus on switching on the capacity of existing stem cells.
Applications of stem cells into autoimmune diseases are currently being actively sought. Autoimmune diseases result in the patient's own immune system attacking its own tissues. The symptoms of the particular autoimmune disease match the type of tissue that is under attack. For example, autoimmune antibodies to a nerve receptor can result in progressive paralysis.
For stem cell therapeutics, one approach is to try to suppress the patient's native immune system, which is attacking the patient, and then replacing bone marrow with other grafted stem cells. Human clinical trials using high dose immunosuppression and chemotherapy, combined with autograft hematopoietic cell transplants have been used in several autoimmune diseases including: systemic sclerosis, rheumatoid arthritis, myasthenia gravis, systemic lupus erythematosus and multiple sclerosis (Burt, 2003; Popat, 2004; Tyndall, 2005). Results and protocols varied among the trials in terms of such things as preconditioning regimens, purging of T-cells and sources of the stem cells. Results from phase I and phase II clinical trials indicate that the approach is feasible and may result in a remission (Burt, 2003; Popat, 2004; Tyndall, 2005). Furthermore, for those patients in whom there is a relapse of the autoimmune disease, many responded to agents that were ineffective before the stem cell therapy (Tyndall, 2005).
Some diseases seem to have longer remissions while others have more frequent recurrences (Tyndall, 2005). There is controversy about the role of T-cells and B-cells in the cause of the autoimmune disease and to what degree purging of T-cells improves outcome before harming the patient secondary to infectious disease (Tyndall, 2005). Phase III trials currently underway in Europe and the USA should help clarify these issues (Sykes, 2005).
Rheumatoid arthritis is a common autoimmune disease in which there are antibody complement complexes causing inflammation of the joints. There are sometimes accompanying extra-articular manifestations such as arteritis, scleritis, pericarditis, splenomegaly or neuropathy.
Stem cell treatments for rheumatoid arthritis are well into human clinical trials. One approach is the chimeric anti-autoimmune strategy. In one trial for a patient with severe, refractory rheumatoid arthritis, the patient was first conditioned with cyclophosphamide, anti-CD52 (which recognizes T-cells and B-cells) and an antimetabolite called fludarabine. The patient then received an allograft transplant of HLA-matched hematopoietic cells that resulted in chimerism among the T-cells and myeloid cells. At the follow-up, one year post-procedure, the patient was in remission, did not have graft-versus-host disease and did not need immunomodulating medications (Burt, 2004).
Multiple sclerosis is a recurrent demyelinzation of the central nervous system, resulting in progressive neurological debilitation. Symptoms are usually waxing and waning in nature, and typically include visual loss, nystagmus, paresthesia and weakness.
The exact pathological cause of multiple sclerosis is unknown. Some theorize a viral source, but most theories include either a full or partial autoimmune reason. For this reason, hematopoietic stem cells might show therapeutic promise for multiple sclerosis (Sykes, 2005). Similar to other autoimmune diseases, autografted hematopoietic stem cells would be harvested, modified, and then reimplanted into the patient who was been made immunocompromised.
The clinical challenge in multiple sclerosis is that the recent pathological findings reveal the cause of the disease to be not just a pure lack of oligodendrocyte progenitor cells that could be easily replaced with new stem cell-derived oligodendrocytes. Rather, the disease seems as though it may be a malfunction of the axons themselves degenerating (Lassmann, 2005).
Use of stem cells in heart disease has been a flurry of active research since heart disease ranks highest in mortality in many western countries. The net result is that cardiovascular usage of stem cells is well advanced into the stage of human clinical trials.
There are three main stem cell candidates that could be used in cardiac therapy: skeletal myoblasts, cardiac stem cells and bone marrow stem cells. While a fourth approach, differentiated cardiomyocytes have showed some results in animal models (Reffelmann, 2003), their therapeutic use is severely hampered by the fact that cardiomyocytes are post-mitotic and thus unable to divide ex vivo (Shim, 2004).
Skeletal myoblasts were the initial choice because they were easy to culture in high numbers in vivo and were resistant to the ischemia that is seen in a myocardial infarct (Murry, 2002). However, there are significant negatives to using skeletal myoblasts. They lose their ability to contract concertedly. They don't from the gap junctions between cells that heart cells use to couple properly (Hegege, 2003), resulting in electromechanical isolation from the surrounding cardiomyocytes (Leobon, 2003). Most concernedly, they can also induce fatal arrhythmias (Passier, 2003). The MAGIC randomized clinical trial in Europe will reveal more about the actual benefits of skeletal myoblasts.
Resident cardiac stem cells are another approach. Their clinical importance increased in light of findings seen in aortic stenosis. In aortic stenosis, the size of the outgoing aortic opening is reduced, forcing the heart muscle to grow bigger to be able to pump the blood out. Evidence has demonstrated that this hypertrophy of heart muscle occurs through intense formation of new cardiomyocytes that have arisen from cardiac stem cells (Urbanek, 2003).
Bone marrow stem cells are currently the favored therapeutic choice for heart. There is a theoretical advantage in that the bone marrow stem cells can differentiate into all three of the major cell types in the heart, namely smooth muscle, cardiac muscle and angioblasts (Shim, 2004). The mechanism of its actual clinical effect is very much a matter of controversy. Initially, it was thought that the bone marrow stem cells would transdifferentiate into cardiomyocytes, though this has been recently challenged (Murry, 2004). It is well accepted that arteriogenesis plays a role in heart repair after injury such as ischemia and that it is dependent on certain growth factors. A recent study indicates that bone marrow stem cells promote angiogenesis by releasing local cytokines in a paracrine fashion (Kinnaird, 2004). Armed with this knowledge, it could be that the actual mechanism is that bone marrow stem cells release cytokines that either activate resident cardiac stem cells or recruit other progenitor cells to repair cardiac muscle (Perin, 2004).
Although bone marrow is the currently favored choice, head to head trials are still pending. It is also possible that the best therapeutic results may come from some combination of stem cells from bone marrow, skeletal muscle or cardiac muscle (Perin, 2004).
The primary focus of cardiac therapy has been acute myocardial infarction, though many of the findings also apply to other cardiac conditions, like congestive heart failure (CHF).
Acute myocardial infarct is the sudden loss of blood supply to heart muscle, commonly termed “heart attack”. It is often as a result of a clot in the coronary arteries. Stem cell therapy is a good choice here, since the muscle is newly damaged and as discussed earlier, this is the type of injury that recruits new cell growth.
Animal studies have shown stem cells can be introduced into an animal's infarcted heart with beneficial effects (Rafii, 2003). The capillaries become denser, apoptosis of the myocytes is decreased and the infarcted area becomes more perfused. All of these result in a net decrease in infarct size (Lee, 2004).
There are three main ways of transplanting stem cells into the heart: intracoronary, intramyocardial and transendocardial. The more popular technique is the intracoronary technique, in which they are infused into the coronary vasculature. There are some suggestions from animals that in the intracoronary technique, the stem cells can clog the small blood vessels of the heart causing microinfarcts (Vulliet, 2004). Partially because of this clogging reason, the intracoronary technique usually uses bone marrow stem cells over skeletal myoblasts, since the latter are too large (Siminiak, 2003). Intramyocardial inserts the cells into the heart muscle directly. The final method is to insert the stem cells through the wall of the heart in a transendocardial technique (Perin, 2003). The transendocardial technique offers the advantages of more precise guided targeting, and is relatively easier when injecting skeletal myoblasts into scar tissue (Perin 2004).
The first of the important human trials is the Transplantation of Progenitor Cells and Regeneration Enhancement in Acute Myocardial Infarction (TOPCARE-AMI) clinical trial (Assmus, 2003; Britten, 2003). In this trial, patients either had an intracoronary infusion of bone marrow mononuclear cells or an intracoronary infusion of endothelial progenitor cells. The stem cell recipients improved cardiac function, as assessed by left ventricular ejection fraction, compared to nonrandomized controls. A subgroup showed reduced infarct size on magnetic resonance imaging (MRI) (Britten, 2003). The TOPCARE-AMI study was followed by a true randomized control trial called the BOOST trial. In the BOOST trial, patients were randomized to either receive bone marrow mononuclear cells or to receive no treatment. Heart function, as measured via left ventricular ejection fraction, was improved in the stem cell recipients (Wollert, 2004). Similar positive findings have been found in anther study using with allografted bone marrow mesenchymal stem cells instead of mononuclear cells (Chen, 2004). Complete cross-reference charts are available, comparing findings of all major recent myocardial infarct stem cell clinical trials (Shim, 2004), including such details as outcomes and whether the stem cell transplant was accompanied by another therapy such as a coronary artery bypass graft.
A final consideration is that any stem cell therapy for a myocardial infarction would likely need to be exactly timed. If the stem cells are grafted too early into the infarcted heart, they are at risk of dying. If they arrive too late, they may not work, as the infarcted heart would be fully remodeled already (Li, 2001; Sakakibara, 2002). Stem cells take a while to extract and culture, a delay that could cause this precise time window to be missed. Therefore, in the future, patients at known risk of a heart attack might have their stem cells extracted and frozen in advance, ready for their myocardial infarction event later (Shim, 2004).
Diabetes mellitus is a chronic metabolic disease of insufficient insulin, causing symptoms including hyperglycemia, glycosuria, ketoacidosis, coma, neuropathy, nephropathy, retinopathy and increased susceptibility to infection. There are two types of diabetes: diabetes type I and type II. Type I usually strikes before age 25, causing autoimmune destruction of beta-cells, resulting in a patient's full dependence external insulin for long-term survival. Type II usually strikes later in life, arising through a combination of insulin resistance and decreased insulin secretion by beta-cells. Whereas type I always requires external insulin, type II diabetics may use oral medications for glucose control, until late in the disease process.
Diabetes is an excellent choice for stem cell therapy because it is a common, chronic disease with serious morbidity and mortality. In some industrialized countries, continuing medical care for diabetes is the largest cost to the health care system. The stem cell therapy very much does not have to be completely curative to be successful. If it can stabilize the disease progression until the patient passes from other disease, or can bring a type II diabetic currently on injected insulin back onto oral medications, stem cells have therapeutic value.
It has been shown that embryoid bodies from mice embryonic stem cells can be made to differentiate into functional pancreatic beta-cells (Lumelsky, 2001), and that manipulation of various culture conditions increases the yield of usable beta-cells (Kahan, 2003; Kania, 2003; Stoffel, 2004). There is some controversy about whether these beta-cells derived from stem cells are precisely the same as normal beta-cells (Sipione, 2004), but characteristics are very similar. However, some critics have challenged that human cells derived from embryonic stem cells currently don't have sufficient controlled release of insulin in response to high glucose (Rajagopal, 2003; Segev, 2004).
Key transcription factors have been uncovered called pdx-1 and pax4 that help shape an embryonic stem cell into a beta-cell lineage (Blyszczuk, 2003; Miyazaki, 2004). It may be more beneficial to slowly turn on these transcription factors when growing the stem cells in vitro, than to give high does of the factors early on in differentiation (Miyazaki, 2004).
In mice, transplanted bone marrow results in donor-derived cells in the islets of the pancreas, first appearing in one to two months post-implantation. In vitro, these donor-derived cells can have calcium fluctuations similar to beta-cells, and can secrete insulin in response to glucose levels (Ianus, 2003). It seems that cell fusion doesn't play as much of a part in marrow-to-pancreas transdifferentiation as it does elsewhere (Ianus, 2003; Hess, 2003).
Similar to other bodily tissue, it appears that repair of pancreatic injury can be aided by stem cell transplantation. In an experiment with mice, the pancreas was severely damaged by the chemical streptozotocin, making the mice overtly diabetic. Transplanted bone marrow cells then caused proliferation of pancreatic cells. Most of these were endothelial cells and a few were insulin-expressing cells. The mice had restored insulin production, lowered hyperglycemia and improved survival, in comparison to the control mice (Hess, 2003).
In addition to the usual candidates of bone marrow and embryonic stem cells, other prospects are progenitor cells in the pancreas and the liver. In mice, liver-resident stem cells can be transplanted and subsequently reverse hyperglycemia (Zalzman, 2003). For the pancreas, there is evidence that there is a pancreas-resident progenitor for many of the different component pancreatic tissues, such as the glands that secrete digestive juices (Zulewski, 2001). However, an actual pancreatic progenitor for the diabetes-relevant beta-cells has yet to be found. Moreover, experimental evidence suggests a pancreas-resident beta-cell progenitor does not exist and that instead of stem cell differentiation, beta-cells form by self-duplication of existing beta-cells (Dor, 2004).
Diabetes type I has an additional problem because of its autoimmune nature. Since the underlying mechanism is not corrected, there is a risk of autoimmune destruction of any newly transplanted cells. Some early work in mice suggests that transplants from the mesenchyme of the spleen may help keep autoimmune destruction in check enough to reverse the process (Ryu, 2001; Kodama, 2003), however it remains a difficult challenge. The encouraging incentive is that immunological evidence shows that in human beings with a new onset of diabetes type I, early intervention with antibody medications can allow the pancreas to recover (Herod, 2002; Glant, 2003). Taking into account the aforementioned suggestion that beta-cells only duplicate from existing beta-cells (Dor, 2004), it could explain the findings: intervention to protect the existing beta-cells from autoimmune destruction allows the beta-cells to self-replicate and thus recover.
An interesting novel approach is to culture the differentiated insulin-producing cells, and then transplant those cells not into the pancreas, but a more easily accessible ectopic site. This has been tried in diabetic mice, transplanting the differentiated cells under the kidney capsule. The insulin-producing cells in the kidney could correct the glucose levels, and excising the kidney graft then returned the mouse back into a diabetic state (Oh, 2004).
Liver disease is a common disease, having several causes including chemical damage, alcoholism and infection. However, the liver does have the advantage that the liver is a fusogenic organ for stem cells, and that hepatocytes are readily cultured from bone marrow cells. The technology for culturing hepatocytes has been available for several years (Theise, 2000). Furthermore hepatocytes of donor origin have been confirmed in recipients of peripheral blood stem cells (Korbling, 2002). It is hoped that stem cell therapies can help shorten the queue for liver transplants.
Stem cell therapy for inflammatory bowel disease (IBD) is still in its very early stages (Thiese, 2005). IBD is an acute or chronic inflammation of the mucosal layers of the intestine. The epithelial lining of the intestinal tract is constantly being shed and renewed, using a stem cell lineage system similar to the bone marrow's hematopoietic stem cell system. The stem cells lie at the bottom crypts of villi that line the intestinal wall and daughter cells then differentiate as the migrate up the villi (Marshman, 2002).
It is known that isolated hematopoietic stem cells in vitro can reconstitute, among other things, epithelia of the gastrointestinal tract (Thiese, 2005). Two experiments cleverly showed that transplanted hematopoietic cells could regenerate the epithelial lining in a patient. The experiments looked at women who had received therapeutic marrow transplants from men. Since women sex chromosomes are XX, when the isolated tissue from the women's intestinal wall showed a Y chromosome in 5 to 7 percent of the enterocytes, it was shown that they must have originated from their male bone marrow donors (Korbling, 2002; Okamoto, 2002).
The advantage with IBD is that it is an inflammatory process, and inflamed tissue is one of the triggers that appear to recruit circulating stem cells. From a therapeutic standpoint for IBD, this raises the possibility of treating an IBD patient with stem cells that are able to secrete an IBD alleviating medication such as antibodies that can neutralize tumor necrosis factor (TNF). The stem cells would then be recruited into the intestinal wall, locally secrete the TNF antibodies, soothe the inflammation of the bowel and thus control the symptoms of IBD (Brittan, 2002).
Stem cell therapy is extremely useful in skin transplantation. When enough layers of the skin are destroyed, the skin cannot regenerate from below. It instead must grow in from the edges. Therefore, transplants are needed for large swatches of destroyed skin, since otherwise it would take too long to grow in from the edges, and there would be cosmetic and infectious problems. In the past, a burn patient with a massive burn area would often require an autograft transplant to prevent rejection of the new tissue, creating a second scar from the donor site on the patient's body.
Stem cells could instead reduce that donor site to a small skin biopsy. The skin stem cells from the biopsy would be grown up in vitro into large sheets on a raft of growth factor proteins designed to induce differentiation into the desired skin type. These sheets, each several layers thick, could then be transplanted onto the burn site.
The technology could be used for not just burns, but all skin transplants, such as unresolving varicose ulcers (Mummery, 2004).
Stem cell research is involved in many other diseases other than the ones described above. This includes everything from Alzheimer's disease to Parkinson's to multiple myeloma to urinary incontinence (Bhatia, 2004).