CHAPTER 2: Hematopoiesis

Jon C. Aster; David Scadden

INTRODUCTION

LEARNING OBJECTIVES

After studying this chapter you should know:

The developmental origins of the blood-forming tissues.
The properties and functions that define hematopoietic stem cells.
The role of growth factors and transcription factors in the regulation of hematopoiesis.
The therapeutic roles of growth factors and hematopoietic stem cell transplantation.

In Chapter 1, we introduced the morphologically recognizable marrow progenitors and their progeny, the red cells, white cells, and platelets that make up the formed elements of the blood. Here we turn to the topic of hematopoiesis (from the Greek "to make blood"), the process by which these elements are created. As we will discuss, hematopoiesis depends on rare, morphologically inconspicuous progenitor cells that have remarkable functional properties. Unraveling how hematopoiesis is maintained and regulated has provided a paradigm for understanding the biology of tissue stem cells and has resulted in the development of effective therapies for certain cancers and genetic disorders as well as a variety of conditions in which bone marrow output is inadequate to maintain normal blood cell counts.

DEVELOPMENT OF BLOOD-FORMING TISSUES

The developmental origins of hematopoietic cells are complex and incompletely understood. Cells with the properties of hematopoietic stem cells (HSCs; described in the following section) arise several times in different tissues during prenatal development, producing successive waves of hematopoiesis (Fig. 2-1). Hematopoiesis first appears around day 16 of gestation in the embryonic yolk sac; at this site, it is limited to the production of red cells, which are needed for oxygen transport in the newly developed circulatory system. Hematopoietic cells arise anew around 3 to 4 weeks of gestation in a portion of the ventral mesoderm referred to as the aorta-gonad-mesonephros region. HSCs derived from this region (and possibly the yolk sac as well) are believed to migrate through the blood and take up residence in the liver, which becomes a hematopoietic organ at around 6 weeks of gestation and serves as the major source of hematopoietic cells throughout much of fetal development. HSCs and some hematopoietic progenitors also appear by around 6 weeks of gestation in the placenta and umbilical cord blood and persist in these sites until birth. By 7 to 8 weeks of gestation, lymphoid progenitors derived from the liver begin to seed the newly developed thymus, which is the major site of T-lymphocyte development. Around 5 months of age, HSCs derived from the liver (and possibly other sites) home to the bone marrow, which becomes the dominant source of hematopoietic elements by birth, around the time that hepatic hematopoiesis ceases.

FIGURE 2-1

Ontogeny of human hematopoiesis. Dotted lines indicate migrations of hematopoietic stem cells or early progenitors that are suspected but not proven.