Hematopoietic Lineages And The Control Of Cell Production

Blood comprises approximately 55% liquid and 45% cellular material and fulfills many recognized functions in mammalian physiology. The most important of these is oxygenation of bodily tissues followed by an important secondary function in combating disease, particularly infectious disease, via both cell-based and humoral mechanisms.

Blood has been the subject of scientific inquiry from prehistory and because of its ready accessibility and liquid nature has lent itself to early dissection of both organization and function. In the early part of the 20th century, Carnot pioneered the idea that blood composition was controlled by a humoral factor (1), which was ultimately identified as erythropoietin (EPO). This work was founded on the observations made by Viault (2), who followed changes in red blood cell count as he and his traveling companions (human and animal) ascended to altitude. From early in the last century it was thus suspected that blood composition may be subject to change in response to environmental variation and that humoral factors may be the mediators of this effect.

The cellular constituents of blood had, of course, been observed by Anthony van Leeuwenhoek in the 17th century in one of the first applications of his newly invented microscope. Hence, the idea that there are various types of blood cells and that their production is under humoral control is not really new, nor is it confined to the era of recombinant proteins, which began in the 1970s. However, that epoch did provoke unprecedented advances in understanding cytokines in general and hematopoietic cytokines in particular, culminating in the cloning of the first hematopoietic cytokine [interleukin-3 (IL-3)] in 1984 (3).

Understanding the basis of cellular diversity in blood had meanwhile undergone equally important advances with the description of the first quantitative assays for murine hematopoietic "stem" cells in 1961 (4). Although spleen colony-forming units (CFU-S) first described by Till and McCulloch were ultimately demonstrated not to exhibit all of the hallmark properties that characterize the most primitive hematopoietic stem cells (i.e., most CFU-S lacked lymphoid differentiation potential and exhibited only a limited capacity for self-renewal), this assay and the cell type it detected is viewed by many to have ushered in the modern era of stem cell biology. The first in vitro colony formation assays for hematopoietic progenitor cells were described in 1965 and 1966 (5,6). In these assays, bone marrow cells that were otherwise unrecognizable were cultured in semisolid medium in the presence of crude preparations of body fluids, tissue extracts, or medium "conditioned" by various cells. Since these extracts (and later their components) stimulated the formation of blood cell colonies, they acquired the descriptive name of "colony-stimulating factors" (CSFs) and their cell targets, the equally unsurprising epithet "colony-forming cells."

Although spectacular progress had been made in the three previous decades, work in the early 1990s provided a remarkable leap in our insight into the organization and control of hematopoiesis; an understanding that to date has still to be equaled for any other tissue in the body. The hematopoietic cell hierarchy, as it was defined at that time and as it is still understood today, is represented by, at its root, a self-sustaining stem cell pool. Maintenance and selected expansion of this pool occurs through processes of asymmetric cell division, and some would say deterministic, others would say stochastic, cell fate decisions that yield a heterogeneous pool of differentially committed progenitor cells. At one extreme, these precursor cells may have the potential to develop into any of the six blood cell lineages, and at the other extreme, they may be capable of responding in one of only two ways—either by dying (a process referred to as apoptosis) or by developing into a single type of mature blood cell. Stem cell self-renewal is largely regulated by intracellular transcription factors that control the expression of an array of "sternness" genes. Oppositely, later processes of hematopoietic development are under the control of extracellular humoral regulators—variously called the CSFs, growth factors, interleukins, or cytokines. These cytokines act either alone or in concert to control the number and type of blood cells that are produced. Some of them act on relatively primitive cells with multilineage differentiation potential [e.g., IL-3 or stem cell factor (SCF)], while others act only on more committed cells in the later stages of blood cell production (e.g., EPO).

Many of these cytokines have been purified and cloned and are available in pharmaceutically useful quantities in recombinant form. Since they are large molecules that cannot be absorbed intact through the gut or skin, recombinant cytokines must be administered via intravenous or subcutaneous injection. While some of these cytokines have been deployed as therapeutics used in millions of patients, others have found little application in medicine and have thus far remained useful only as laboratory reagents or research tools. Of those that have found clinical utility, several have been reengineered to enhance their drug-like attributes, while others remain essentially identical to the native proteins purified from tissue sources.

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