Читать книгу The SAGE Encyclopedia of Stem Cell Research - Группа авторов - Страница 148

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Blood Adult Stem Cell: Existing or Potential Regenerative Medicine Strategies

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Blood Adult Stem Cell: Existing or Potential Regenerative Medicine Strategies

Regenerative medicine is a branch of medicine that focuses on the generation of viable cells, tissues, or organs or the use of cells to achieve a therapeutic outcome (e.g., to decrease inflammation in many disease processes). In response to the increasing burden of diseases caused by aging, trauma, sequealae (injury caused by disease or treatment), and congenital defects, new advances in regenerative medicine are paving the way for more effective treatments.

Current emphasis on stem cell therapies (embryonic and adult), a foundation for the generation of viable cells, tissues, and organs, has resulted in many new potential treatments. Because of the many ethical concerns in using embryonic stem cells, which are obtained from embryos, adult stem cells are at the forefront of recent studies ranging from bone marrow transplants in cancer patients and regeneration of cardiac tissue after myocardial infarction (MI-heart attack) to regrowth of bone in orthopedic disorders.

Adult Stem Cells

In contrast to embryonic stem cells, which are obtained from a developing embryo, adult stem cells are postnatal stem cells residing in the blood, bone marrow (BMCs), organs, and tissues. They are multipotent (limited differentiation potential) and can have a limited life span. Recently, scientists discovered that human adult stem cells derived from several sources (including blood) can be genetically reprogrammed to become the pluripotent equivalent of embryonic stem cells, with the ability to change into any cell type, thus potentially increasing the number of diseases that can be treated. Some disadvantages of using adult stem cells is a lack of guidelines on harvest volume of cells, timing in the course of a disease process to administer the cells, as well as optimal location of injection (e.g., heart muscle or vascular for cardiac injury). Additionally, stem cells harvested from an individual can carry harmful genetic mutations.

Specific blood-associated stem cells currently being used in Regenerative Medicine research are hematopoietic stem cells (HSC-bone marrow), mesenchymal stem cells (MSC-multiple tissues, including bone marrow and blood), and endothelial stem cells (ESC-bone marrow), and these are the most easily accessed. Some of these cells are also found in umbilical cord blood (UBCs), and these have many benefits. Foremost, if cord blood can be obtained at birth and stored (Cord Blood Registry), it provides a rich source of autologous stem cells that can be accessed in the event of disease or injury. Also, there is a reduced risk of developing graft-versus-host disease (GVHD), which commonly occurs in allogeneic transplants.

In addition to specific cells, there are important enzymes, growth factors, and other components present in stem cell-containing samples that serve to enhance the growth of target stem cells. An example of growth factor is granulocyte colony-stimulating factor (G-CSF). In particular, G-CSF has been used extensively to promote the mobilization or growth of certain stem cells in diseases such as cancer.

Existing Therapies in Regenerative Medicine

Bone marrow-derived stem cells have been in use since the 1960s for treatment of certain blood-related/bone cancers. The primary emphasis was placed on making sure healthy bone marrow could be restored after radiation or chemotherapy destroyed existing bone marrow. However, there are many caveats to receiving autologous (self-donor), allogenic (other donor), or, in rare cases, syngenic (twin donor) bone marrow transplants. First, though transplant rejection is minimized, autologous transplants carry the risk of reintroducing cancerous cells into the body after chemotherapy. Allogenic transplants reduce the potential for introducing mutated cells into the body but carry the potential for transplant rejection. Additionally, hematopoietic stem cells have been used to treat hematological dysfunctions and replenish bone marrow stores after chemotherapy.

A large number of recent studies have been performed on regeneration of cardiac tissue after trauma. After a functionally significant MI, patients can experience a loss of more than 1 billion cardiomyocytes, and surviving cardiomyocytes undergo abnormal remodeling, which eventually leads to heart failure. Current therapies such as medical management of hypertension and stent placement, to limit cardiac damage brought on by these and other cardiac complications, are often inadequate in optimizing cardiac health.

In 2012, the Cardiovascular Cell Therapy Research Network published results on the effect of timing of delivery of stem cell therapy after ST-segment elevation, an indication of heart attack. The BMCs or placebo were injected into the heart after a confirmed heart attack, either three or seven days after reperfusion (i.e., stent placement). Change in left ventricular function was evaluated after six months. They concluded that the time-course therapy did not result in a significant change on recovery or left ventricular function compared to placebo.

In a study at Emory University School of Medicine, emphasis was placed on high doses of CD34+bone marrow mononuclear cells (BMMNCs) given to patients after undergoing coronary stenting. At six month’s follow-up, there was a mean improvement (4.5 percent) of ejection fraction, or how much blood the heart is able to pump from the left ventricle (most commonly), in patients who had received at least 10 million cells compared to the low dose group (5 × 10⁸) and control. A randomized, controlled, Phase II, double-blind trial conducted by the University of Texas at Houston evaluated the safety and efficacy of autologous BMMNCs under electromechanical guidance for patients with chronic ischemia (lack of oxygen) heart disease and left ventricular dysfunction. No significant change was observed for any of the parameters of the treatment group compared to control.

Peripheral artery disease, in which the patient has damaged arteries and surrounding tissue due to an obstruction, is also an area of intensive research. Bone marrow-derived and endothelial progenitor cells have been harvested from patients with or without G-CSF mobilization; target cell population(s) are amplified and injected into the patient’s affected limb (usually multiple injection sites around the damaged tissue). Results have been mixed for improved perfusion of the damaged tissue, but collateral growth (new blood vessel growth), increased walking time, and overall limb salvage has been observed in several recent small clinical trials.

Potential Therapies in Regenerative Medicine

In a study by Stessuk and colleagues (2013) in Brazil, it was reported that autologous BMMNCs were administered to four patients with advanced-stage chronic obstructive pulmonary disease, refractory to standard treatments, and limited life expectancy. Baseline spirometry measurements, a measure of lung capacity, were taken prior to baseline. Measurements were retaken at six months follow-up, and the patients were asked about quality of life. It was concluded that improved lung capacity was observed in three of the four patients. Larger studies are now being conducted exploring the potential use of these cells to improve lung capacity and quality of life for several lung disorders and even lung transplant recipients.

Promising research in the area of type 1 diabetes (T1D) is focused on autologous blood stem cells to replenish damaged β-cells. However, even when there is an increase in growth of β-cells, the subject’s immune system continues to attack the new healthy cells. Dr. Habib Zaghouani’s group at the University of Missouri developed Ig-GAD2, a drug designed to inhibit the autoimmune attack on β-cells while simultaneously infusing autologous bone marrow stem cells, which has shown promise in a murine model. During this research, he and his team discovered the administration of the drug and stem cells encouraged the growth of new blood vessels in the pancreas, which helped the β-cells proliferate and thrive. He concluded that β-cells indirectly require new blood vessels in order to continue to grow. A pilot study performed at the University of Florida showed that infusion of cord blood stem cells provided some slowing of the loss of insulin production in children with T1D, evidenced by the reduced need for insulin injections.

Diseases such as Alzheimer’s, for which human cord blood MSCs have been used in animal models, show a reduction of beta amyloid and are currently being investigated in human trials. Neurodegenerative diseases, such as Parkinson’s disease and spinal cord injury, can potentially benefit from use of mesenchymal stem cells. Laboratory studies on cord blood MSCs have shown benefits for liver cirrhosis via enhanced wound healing. Preliminary study results indicate that an infusion of cord blood MSCs promotes the secretion of glucose and insulin, which help improve liver function. Many more uses of cord blood MSCs are being investigated, including bone repair and treatment of congenital heart defects and peripheral arterial occlusive disease.

Given the recent positive results from a large portion of these preclinical and small clinical studies, it is reasonable to state that once the treatment protocols that entail optimum dosage of stem cells, improved identification and isolation methods of the stem cells, and timing and location of administration are standardized, utilization of blood or bone marrow-derived stem cells will be an effective adjunct therapy. In order to demonstrate true efficacy it is also necessary to conduct adequately powered, multicenter, randomized, controlled clinical trials.

Mandy M. McBroom

University of Texas Southwestern Medical Center

See Also: Adult Stem Cells: Overview; Clinical Trials, U.S.: Graft Failure, Graft-Versus-Host Disease; Mesenchymal Stem Cells.

Читать книгу The SAGE Encyclopedia of Stem Cell Research - Группа авторов - Страница 148

Blood Adult Stem Cell: Existing or Potential Regenerative Medicine Strategies

Adult Stem Cells

Existing Therapies in Regenerative Medicine

Potential Therapies in Regenerative Medicine

Further Readings