Blood Disorders | Overview
Bone marrow has the job of creating all blood cells. Red blood cells transport oxygen and CO2 between tissues, white blood cells to fight cancerous cells or infections and platelets to stop bleeding. In healthy individuals, all of these specialized blood cells function normally and they are replaced by new cells that mature from differentiating hematopoietic stem and progenitor cells in the bone marrow. Remarkably, a single hematopoietic stem cell (HSC) can reconstitute the entire hematopoietic system through its unique ability to both self-renew and create diverse progenitor cells that expand and mature into specialized blood cells. Malfunctioning bone marrow, which can produce too few or too many cells, is the cause of many serious diseases of the blood.
Insufficient numbers of platelets, also called thrombocytopenia can cause excessive bleeding. This can result from genetic defects, autoimmune reactions, leukemia or bone marrow failure. Platelet counts in these patients can be normalized by donor platelet transfusion, but fresh donor platelets have a short shelf life and are not always available, and the immune system of some patients does not tolerate them. Human pluripotent stem cell derived platelets offer a potentially unlimited source of immunologically compatible platelets, but they must be made in a cost-efficient manner. The Schlaeger laboratory recently discovered small molecules that make the large-scale production of human pluripotent stem cell derived platelets much more efficient and cost-effective (Ref forthcoming), and companies such as Platelet Biogenesis and Megakaryon are working to make hiPSC-derived platelets available to patients.
Sickle cell anemia
Sickle cell anemia is caused by specific mutations in beta-globin, one of the proteins that make up the oxygen transport molecule hemoglobin in red blood cells. The mutation makes the hemoglobin molecules sticky, causing them to polymerize under low oxygen conditions, which in turn changes the shape and reduces the flexibility of the red blood cells, making it harder for them to squeeze through small blood vessels. The Daley lab, together with the Stem Cell Core Facility, is using hiPSC to study sickle cell anemia. They have fixed the disease-causing mutation in patient-derived hiPSCs and are now developing methods to make large amounts of mature red blood cells in a dish from normal or repaired hiPSCs that could eventually be transfused back into patients. The sickle cell hiPSCs can also be used to find new drugs that reactivate the fetal version of beta-globin that is normally silenced in children and adults but that, when reactivated in patients, will reduce the symptoms of sickle cell anemia. Stuart Orkin, MD, of Boston Children’s discovered that the fetal globin gene is silenced after birth by a repressor protein (BCL11a). Several gene therapy-based approaches to cure sickle cell anemia that leverage this key insight are now being studied at Boston Children’s.
Bone marrow failure syndromes
Stem cell biologists at Boston Children’s also study many other types of anemia and bone marrow failure syndromes. For example, they were the first to successfully generate hiPSCs from patient with Fanconi anemia (FA) in which a critical DNA damage repair pathway is mutated. Patients with FA have too few hematopoietic stem cells, making it particularly difficult to treat them with gene therapy. The ability to make hiPSCs from patients with FA opens the possibility to one day treat and possibly cure these patients with autologous hiPSC-derived blood or blood stem cells. Potential new therapeutic avenues were also discovered by Stem Cell Program researchers for conditions, such as Diamond-Blackfan anemia, Shwachman-Diamond syndrome or dyskeratosis congenita.
Sometimes, normal blood formation goes awry not because of mutations that interfere with specific functions of mature blood cells or because too few mature blood cells are produced, but because too many immature and abnormal blood cells are produced. Leukemia is the most common type of cancer in children. Stem Cell Program researchers use hiPSCs and other models to better understand how the various forms of leukemia develop and how to better treat them.
Some cases of leukemia can be cured by bone marrow or hematopoietic stem cell transplantation, but if the patient’s own blood cells are used, they may be contaminated with leukemic cells. Alternatively, bone marrow from a suitable healthy donor could be used, but it is often not possible to find one that will be accepted by the patient’s immune cells and that won’t attack the patient’s normal cells.
Boosting blood stem cell production
Umbilical cord blood contains blood stem cells, and cord blood banks make it more likely that immune-compatible blood stem cells can be found for a patient, but the number of blood stem cells per cord blood sample is quite low. Trista North, PhD, and Stem Cell Program Director Leonard Zon, MD, have discovered a promising and previously unrecognized way to use the drug PGE2 to boost blood stem cell production in patients undergoing treatment for leukemia or lymphoma. The work started with studies in zebrafish and extended to mouse marrow transplants. In a Phase I clinical trial for leukemia, there were 12 patients treated, and each received two cord blood units. One of the cord blood units was treated with PGE2. The treated cord blood units preferentially engrafted in 10 of 12 patients. A phase II clinical trial has treated 48 patients.
Making blood stem cells from hiPSCs
George Daley, MD, is trying to make blood stem cells more available to patients who need them by creating these precious cells in a dish from patient-derived hiPSCs. They recently achieved several breakthroughs that may soon make it possible to cure patients suffering from leukemia other blood disorders with these custom-made and healthy blood stem cells made from hiPSCs.
Another promising cell-based approach to rid patients of leukemic cells is the use of so-called chimeric antigen receptor T cells. These CAR-T Cells are made from T-cells, a constituent of the immune system that can kill cells it recognizes as abnormal. CAR-T cells are currently made specifically for each patient by isolating T-lymphocytes from a patient, teaching them how to identify and target leukemic cells, and then injecting them back into the patient. To make CAR-T cell-based therapy available to a larger number of patients, the Daley lab is working to streamline this process. They are working on making off-the-shelf CAR-T cells from hiPSCs in a dish.
Other significant blood disease research underway
Scott Armstrong, MD, PhD, an affiliate member of the Stem Cell Program at Boston Children’s, works with leukemia stem cells, which are the subset of cells in leukemia that are responsible for the development and continued growth of the disease. Leukemia stem cells are the critical cells that must be eradicated to cure leukemia.