Hematopoietic stem and progenitor cells (HSPCs) are a small renewable pool of precursors that generate the immune and hematopoietic systems throughout life, present mainly in the bone marrow but also in the blood (including umbilical cord blood. These cells are responsible for the constant renewal of blood and immune system cells (including lymphocytes, monocytes and macrophages, neutrophil, erythrocytes, and platelets).
It is known that a small number of HSPCs can expand to generate a very large number of daughter HSPCs. This phenomenon is used in bone marrow transplantation, when a small number of HSPCs reconstitute the hematopoietic system.
Where are they located?
The physiological site of HSPCs is the marrow of long bones and vertebrae of adults. Approximately 1 in every 10,000 to 15,000 bone marrow cells is thought to be a stem cell. HSPCs may pass the bone marrow barrier, and, thus, may travel in the blood from the bone marrow in one bone to another bone. However, only a small number of stem and progenitor cells circulate in the bloodstream, and their proportion in the blood falls to 1 in 100,000 blood cells. The ability to harvest directly from peripheral blood is augmented by injecting granulocyte-colony stimulating factor (GCSF) prior to harvesting. Stem cells are also found in the umbilical cord blood and are by definition naïve and not stimulated.
How are they identified?
TDespite the vast work and experience with hematopoietic stem cells, their identification is poorly defined. The reason is that HSPCs have different appearances and they tend to change their appearance dynamically especially when taken out of the body. The most accessible identifiers of these cells are which that are used for isolation from heterogeneous samples harvested from donors.
HSPCs are negative for markers that are used for detection of mature blood-lineage, but are positive for the presence of other surface markers such as CD34, CD38 and CD133). The current approach for identification and selection of HSPCc is through markers that appear on the surface of cells. These markers are tagged with monoclonal antibodies bearing a fluorescent label and selected by fluorescence-activated cell sorting (FACS). However, not all HSPCscan be detected by these markers, while some HSPCs may have or lack certain markers on their cell surface. As a result, some HSPCs are missed and some mature cells are always present in any of the currently available HSPC-selection methods, leading to an array of adverse and life-threatening conditions post-transplant, of which the most common is Graft versus Host Disease (GVHD).
Other approaches to isolation are by targeting intracellular molecules prevalent in HSPCs, as well as by following low metabolic state and divisional quiescence. These markers are more difficult to implement in the clinical setting.
Stem Cell Transplantation
Stem cell transplantation (SCT) is a medical procedure in which stem cells reconstruct and replace damaged tissues and organs – a potential cure for a wide range of diseases and disorders. Hematopoietic stem cell transplantation (HSCT) (previously call Bone marrow transplantation – BMT) is a transplantation of multipotent hematopoietic stem cells derived from bone marrow, peripheral blood, or umbilical cord blood. Stem cell transplantations are used to replace bone marrow that has been destroyed by disease (such as cancer or autoimmune disease), or treatment (such as chemotherapy or radiation therapy). HSCTs have improved substantially over the last decades; however significant morbidity and toxicity of this procedure preclude its wide therapeutic use. HSCTs are currently performed as a last-resort for intractable hematological malignancies and on a limited basis to correct inborn immune deficiencies.
These indications account for 95% of the 50,000 stem-cell transplantation procedures performed each year worldwide. Despite rapid expansion in use and constant evolution in technology, stem cell transplantation remains a risky procedure with many potentially fatal complications, and indications for use are still restricted to patients with life-threatening diseases.
Types of stem cell transplantations for treating cancer
An autologous stem cell transplantation involves transplantation of the patient’s own HSPCs, harvested prior to chemotherapy or radiotherapy. After the cancerous bone marrow has been eradicated, the patient’s own stem cells are returned to the body to replace the destroyed tissue and resume normal blood and immune cell production. An autologous stem cell transplantation is the least toxic transplant, recovery is fast and the graft is not rejected, yet the capacity of the self immune system to combat cancer and some autoimmune disorders is restricted – in these patients the immune system has already failed once to control the disease. In patients with hematological malignancies the autologous graft has to be purged of cancer cells, and even then the cure rate is reduced.
Allogeneic stem cell transplantation
In this case the stem cells originate from a healthy donor, whose tissue typing matches that of the patient to some degree. The donor can be either a family member or a matched unrelated donor. Cells are collected for transplantation from three main sources: blood progenitor cells mobilization from the bone marrow (mPB), the bone marrow (BM) and umbilical cord blood (UCB). Prior to infusion of HSPCs the recipient will require conditioning or a preparative regimen of chemotherapy and/or irradiation to help eradicate the disease and suppress immune reactions. An advantage of allogeneic stem cell transplantation is that the donor stem cells create their own immune cells, which may help destroy any cancer cells that may remain after the preparative treatment by chemotherapy or irradiation. This is called the Graft-versus-Tumor effect (GVT). Despite significant advances in adjuvant therapies and transplant procedures, these transplants have significant toxicity and morbidity and expose the recipient to life-threatening complications.
The main disadvantage is the risk of developing a condition known as Graft-versus-Host Disease (GVHD), in which the immune cells from the donor can attack the patient’s body. Following the conditioning, having no immune defenses, patients become vulnerable to various infections. Even when the transplantation is successful, the need to continuously suppress the immune system because of the GvHD exposes these patients to high risk for infections. Another well-known risk is the potential rejection by the patient’s residual immune system. Taken together, even successfully transplanted patients will suffer lifelong critical risks.
This newer form of treatment uses lower doses of chemotherapy and irradiation as part of the preparative regimen, with the intention of killing only some of the cancer and host bone marrow, and suppressing the immune system just enough to allow donor stem cells to settle in the bone marrow. Slowly, over the course of several months, the donor’s T-cells eradicate the remaining recipient HSPCs and induce the desired graft versus tumor effect. Mini-transplantations run lower risks of serious infections and transplant-related mortality, allowing patients who are considered too high-risk for conventional allogeneic HSCT to undergo a procedure, which by definition, carries a higher risk of both rejection and tumor recurrence.
Graft versus Host Disease
Graft versus Host disease (GvHD) is a common complication of allogeneic (non-related) as well as haploidentical (family member) stem cell transplantations in which T-cells present in the graft launch an attack on the host. GvHD reactions are very common, and in most cases they create a debilitating chronic disease which requires continuous immune suppression and may evolve into a life-threatening acute disease. GvHD is the most serious drawback of bone marrow transplantation and the main reason why this life saving procedure is currently used only for life threatening conditions (mainly cancer).
Types of GvHD
Treatment of both acute and chronic GvHD generally includes a regimen of intravenously administered corticosteroids, such as prednisone, to suppress the T-cell-mediated immune attack, as well as chemotherapeutic agents. However, these drugs have their own severe complications of which the most prominent is suppression of the patient’s immune system, making the patient vulnerable to infections and increasing chances of tumor reoccurrence.
The risk of GvHD can be decreased by removing the T-cell population from the donor stem cells prior to transplantation. Since a small fraction of T cells is beneficial for engraftment and anti-tumor effect, researchers are looking for ways to selectively eliminate the harmful T cells based on their GvHD potential rather than complete depletion using phenotypic markers. Such a selection would reduce the likelihood of GvHD, while allowing the donor T-cells to destroy any cancer cells that may be left.