The process by which bone marrow stem cells make blood cells is called “hematopoiesis.” All blood cells arise from one multipotent stem cells known as the “hematopoietic stem cell” or HSC. HSCs are found in bone marrow and they are the basis of bone marrow transplants.
The first bone marrow transplant was done in 1957 by Donnall Thomas. Unfortunately, this patient died as a result of “graft versus host disease,” in which the immune cells from the transplanted bone marrow attack the tissues of the recipient. With the advent of tissue typing, the first successful bone marrow transplant was done in 1968, and since that time, bone marrow transplants have been used to treat leukemia, aplastic anemia, lymphomas such as Hodgkin’s disease, multiple myeloma, immune deficiency disorders and some solid tumors such as breast and ovarian cancer. Because treatments can wipe out hematopoietic stem cells, bone marrow transplants can replace them.
Fortunately, bone marrow is not the only source of HSCs, Umbilical cord blood from new-born babies also has a robust HSC population. The disadvantage of using cord blood HSCs is that the volume of cord blood in the umbilical cord is quite small compared to the material available from a bone marrow aspiration. However, umbilical cord HSCs are capable of higher rates of cell division, since they are more immature than their bone marrow counterparts. During development, HSCs divide and increase in numbers in the fetal liver. The HSCs reside there until shortly after birth. After birth, the HSCs begin to mature but still show increased growth capabilities that are greater than those from bone marrow HSCs.
HSCs form hematopoietic progenitor cells (HPCs), which have a lower capacity to divide and differentiate. The ability of HPCs to form blood cells is determined by means of a “colony forming cells assay” or CFC. In this test, the HPCs are placed on a plastic culture dish filled with a semi-solid medium that is laced with particular growth factors that are known to stimulate the formation of blood cells (cytokines). HSCs are usually assayed in a living animal, but a laboratory test does exist for HSCs called the long-term culture-initiating cell (LTC-IC) assay. This test, and others, do a pretty passable job of determining the health and effectiveness of a batch of HSCs to reconstitute the bone marrow of an organism, at least in mice, but how well these tests work for human cells is not as clear-cut as they are for the mouse.
One successful assay for human HSCs involves reconstitution of the bone marrow of laboratory animals that have been exposed to lethal doses of ionizing radiation. The blood-making capacities of these animals can be completely reconstituted by infusing human HSCs into them. Sheep are one of the large animals of choice, but mice are equally as valuable even though the mouse model may not completely accurately predict the behavior of HSCs in larger animals.
Mice that carry a mutation called the Prkdc mutation can have their bone marrows completely reconstituted by human HSCs after lethal irradiation, and such mice now have a blood cell-making system that is completely human in nature. Introduction of other mutations can make the immune systems of these mice even more human-like, and such mice are models for the study of a variety of immune system diseases.
How does one identify a HSC in bone marrow or umbilical cord blood? It has a protein on its surface called CD133. There is also an enzyme that is found in HSCs that isn’t found in other blood cell types (aldehyde dehydrogenase). HSCs also have the ability to exclude a toxic dye called Hoechst33342, which also distinguishes them from other cells.
Umbilical cord blood HSCs grow much faster than HSCs from adult bone marrow, and therfore, 20-fold fewer cells are required to reconstitute the bone marrow if umbilical cord HSCs are used. However, when given to a recipient, donated HSCs must home to the bone marrow in order to take up residence there. Unfortunately, umbilical cord HSCs do not home as well as those from bone marrow. They do not express some of the genes necessary for homing at high levels, and this impedes them from finding their way to the bone marrow. Experiments with engineered umbilical cord HSCs that express some of the genes required for homing at higher levels have proven successful in animals. Also, introducing such cells directly into the bone marrow can also deposit the umbilical cord HSCs where they need to be.
Umbilical cord HSCs are a potent source of HSCs for clinical work, and with the banking of umbilical cord blood, more and more of these cells are available for clinical use. While they are not a perfect source of treatment for various maladies, they offer a possible treatment where, in the past, no such treatment possibility existed. The graft versus host response is a genuine possibility when umbilical cord blood is used. However, umbilical cord-based treatments are becoming more and more important in the treatment of many maladies and the importance of these cells has only just begun to be realized.