Programming towards the Hematopoietic Stem Cell Lineage

Abstract

WITHIN the physiology of all vertebrate animals, the cells of the blood tissue function as a transport system for oxygen and nutrients, to remove cellular waste, and to protect against pathogens. The hematopoietic system consists of a hierarchy of different cell types. At the base of this hierarchy is a population of very rare cells named hematopoietic stemcells (HSCs). The HSCs are functionally distinct from all hematopoietic cells by two important properties; (1) they can generate all the different blood cell types (multipotent); (2) they can divide without losing their multipotency (self-renewal). In humans, the continuous daily replenishment of the hematopoietic system by billions of newly formed blood cells highlights the importance of HSC multipotency and self-renewal capacity. The hematopoietic system is one of the best described tissues in mammals. In general, HSCs divide rarely and generate progeny which are more highly proliferative but have a more restricted potential (differentiation). These cells in turn give rise to short lived, terminally differentiated blood cell types. HSCs differentiate to twomain branches of the hematopoietic system: the myeloid branch consisting of erythroid and myeloid sub-branches, and the lymphoid branch. The erythroid cells, also known as red blood cells, are responsible for oxygen transport and are the most abundant cell type present in the blood. The myeloid branch consists of monocytes (macrophages and dendritic cells), granulocytes (basophils, neutrophils, and eosinophiles), and megakaryocytes. Myeloid cells form the first line of protection against pathogens and foreign materials (innate immunity), are involved in removal of damaged cells, and are responsible for clot formation in case of damage to the blood vessels. The lymphoid branch consists of B- and T-cells, and provides long-term memory for protection against recurring pathogens (adaptive immunity). The knowledge we have accumulated in the past years on HSC development and function, has enabled us to treat many diseases of the hematopoietic system. Severe hematopoietic diseases (e.g. leukemia) are often treated by transplantation of HSCs derived from the bone marrow, peripheral blood, or umbilical cord of a compatible healthy donor. HSC transplantations give superior outcomes as compared to other treatments, since they regenerate the complete hematopoietic system of the patients, providing long-termrelief from disease. Recent studies have identified new sources (placenta) for isolation of HSCs and have gained a limited success with ex vivo expansion of HSCs (Alvarez-Silva et al., 2003; Robin et al., 2009;Walasek et al., 2012). However, lack of compatible donor HSCs, and inability to expand available HSCs ex vivo to reach HSC numbers required for long-term regeneration, is still a major obstacle to the wide-spread use of these cells for treatment of hematologic diseases. Therefore, a better understanding of HSC development will help us to identify the conditions necessary for ex vivo HSC expansion and or de novo generation of HSCs.