Exploring the Hematopoietic Stem Cell:  the prototype

(A LAY REVIEW)

The hematopoietic stem cell (HSC) is a stem cell which mainly resides in the bone marrow with its primary function being to produce and maintain the blood and immune cells of the body (see table 1 and figure 1).  The defining characteristics of the hematopoietic stem cell are their ability to renew themselves for the entire life of an organism, to produce different types of specialized cells, and to circulate around the body.  The determinants of these various activities are chemical signals and factors which are present in the surrounding environment of the HSC.  Specific markers on the surface of these cells are used to identify and separate them from cells of similar size and shape.

In 1917, Pappenheim proposed the existence of an undifferentiated stem cell giving rise to the excess of blood cells via an intermediate state of progenitor cells. Throughout the 1950s, several groups did experiments with irradiated mice that had their bone marrow depleted and transplanted with new bone marrow.  Results from these experiments supported the existence of hematopoietic stem cells (HSC) from the hematopoietic recovery in the transplanted bone marrow and thus began the search to isolate human HSC. The tracking of HSC using antibodies for cellular markers helped in delineating the pivotal roles played by many of the regulatory cytokines.  The successful cloning of Dolly the sheep from an adult tissue cell helped spur several groups to reevaluate the differentiation capacity of adult tissue stem cells like HSC.

Hematopoiesis is the process of blood cell production, in which billions of blood cells and platelets are produced every day to replenish blood cell loss due to normal cell turnover, illness, or trauma.  Because of this high production rate, many problems may arise during cellular proliferation.  Understanding the process of hematopoiesis and blood disorders that arise from it may point the way to developing safer and easier methods in repairing hematopoietic stem cell abnormalities.  Pathologies of HSCs may arise from age-related disorders or from cancer treatment. 

Many diseases that involve the dysfunction of hematopoietic stem cells may also arise from a genetic basis, such as severe combined immunodeficiency (SCID). Gene therapy clinical trials in SCID-X1 have had varied results:  younger patients have achieved better levels of therapy than older patients, but risks still exist.  The advent of leukemia has raised concern for the future of gene therapy in HSCs.  While models of this leukemia are being studied in mice, the future of gene therapy in HSCs is uncertain.  Meanwhile, new technologies, such as expression profiling using microarrays, are being developed to better understand the inner workings and mechanisms of “stemness” of HSCs.

Bone marrow transplants have become commonly used to treat hematological disorders since the 1980s.  HSCs used for transplant are usually derived from peripheral blood (PB) or from bone marrow (BM). The collecting, or harvesting, of SC from PB is less burdensome and safer than from BM, in that the donors do not have to undergo general anesthesia or hospitalization, and is therefore, preferred especially for pediatric donors. Autologous transplantation entails the reinfusion of the patient’s own stem cells, which are harvested prior to treatment, and used to repopulate the cells of the bone marrow that were killed by prior treatment with lethal chemotherapeutic agents.  The advantage of autologous transplantation is that no graft rejection, or graft-versus-host disease (GVHD), will occur as does with allogeneic (from a donor) transplantation. 

Studies have suggested that adult HSCs can repair and regenerate certain organs and tissues via transdifferentiation. This indicates that the HSC has developed into a tissue type it normally does not form. These stem cells may have the capability to differentiate into liver cells, epithelial cells of the skin and GI tract, cardiac cells, and endothelial cells.  To date, only HSCs have really been transplanted in humans to successfully regenerate tissue. HSCs continue to be the prototype stem cell being studied to further understand the mechanisms and functions of other kinds of stem cells.

Table 1.  Keywords and definitions.

LT-HSC: Long Term Hematopoietic Stem Cell; A stem cell which has retained it’s
ability to self renew. CD34-

ST-HSC: Short Term Hematopoietic Stem Cell; A stem cell which has lost it’s ability to self-renew. CD34+

MPP:  Multi-Potent Progenitor; Directs stem cell towards either a lymphoid or myeloid lineage.

B-Cell: Lymphocyte which differentiates into anti-body producing cells in response to immunogenic signals.
                       
T Cell:  Lymphocyte which mediates and regulates cellular responses by assisting B-Cells but are incapable of producing antibodies. 

Natural Killer Cell: Lymphocyte which destroy abnormal host cells or invaders.

Macrophage: Phagocytic cell that destroy pathogens and are sometimes involved in immune responses.

Erythrocyte: Red Blood Cell; Hemoglobin/Oxygen carries of the circulation. 

Megakaryocyte:  Multinuclear giant cell of the bone marrow in which portions break off to
                        produce platelets.

Platelet: Cell fragment responsible for blood clotting.

Granulocyte:   Leukocyte (White Blood Cell); Defense role in tumor, viral, bacterial, and parasitic infection.

Neutrophil: Pinocytotic leukocyte involved in complement mediated delayed hypersensitivity reactions. (Introduction of antigen intradermally).

Eosinophil: Leukocyte found at sites of parasitic infections.

Basophil: Leukocyte important in allergic reactions.         

Acknowledgements

This review was prepared by the following graduate students in the Stem Cell Biology Class, Graduate School of Biomedical Sciences, University of Medicine and Dentistry of New Jersey:

Teaching Assistant:  Edward Garay

The review was edited by two stem cell biologists.