Hematopoietic Stem Cells
All of the cell types in the peripheral blood and some cells in every tissue of the body are derived from hematopoietic (hemo: blood; poiesis: creation) stem cells. If the hematopoietic stem cell is damaged and can no longer function (e.g., due to a nuclear accident), a person would survive 2–4 weeks in the absence of extraordinary support measures. With the clinical use of hematopoietic stem cells, tens of thousands of lives are saved each year (Chap. 110). Stem cells produce hundreds of billions of blood cells daily from a stem cell pool that is estimated to be only in the tens of thousands. How stem cells do this, how they persist for many decades despite the production demands, and how they may be better used in clinical care are important issues in medicine.
The study of blood cell production has become a paradigm for how other tissues may be organized and regulated. Basic research in hematopoiesis includes defining stepwise molecular changes accompanying functional changes in maturing cells, aggregating cells into functional subgroups, and demonstrating hematopoietic stem cell regulation by a specialized microenvironment; these concepts are worked out in hematology, but they offer models for other tissues. Moreover, these concepts may not be restricted to normal tissue function but extend to malignancy. Stem cells are rare cells among a heterogeneous population of cell types, and their behavior is assessed mainly in experimental animal models involving reconstitution of hematopoiesis. Thus, much of what we know about stem cells is imprecise and based on inferences from genetically manipulated animals.
CARDINAL FUNCTIONS OF HEMATOPOIETIC STEM CELLS
All stem cell types have two cardinal functions: self-renewal and differentiation (Fig. 92-1). Stem cells exist to generate, maintain, and repair tissues. They function successfully if they can replace a wide variety of shorter-lived mature cells over prolonged periods. The process of self-renewal (see below) assures that a stem cell population can be sustained over time. Without self-renewal, the stem cell pool would become exhausted and tissue maintenance would not be possible. The process of differentiation leads to production of the effectors of tissue function: mature cells. Without proper differentiation, the integrity of tissue function would be compromised and organ failure or neoplasia would ensue.
Signature characteristics of the stem cell. Stem cells have two essential features: the capacity to differentiate into a variety of mature cell types and the capacity for self-renewal. Intrinsic factors associated with self-renewal include expression of Bmi-1, Gfi-1, PTEN, STAT5, Tel/Atv6, p21, p18, MCL-1, Mel-18, RAE28, and HoxB4. Extrinsic signals for self-renewal include Notch, Wnt, SHH, angiogenin, and Tie2/Ang-1. Based mainly on murine studies, hematopoietic stem cells express the following cell surface molecules: CD34, Thy-1 (CD90), c-Kit receptor (CD117), CD133, CD164, and c-Mpl (CD110, also known as the thrombopoietin receptor).