Erythropoiesis: The Roles of Erythropoietin and Iron

1.1

Hematopoiesis

The cellular and cell-derived components of the blood are generated in the process called hematopoiesis. In the adult, hematopoiesis occurs in the medulla of the bone marrow, while some hematopoiesis occurs during early embryonic development in the yolk sac and the fetal liver. Hematopoietic stem cells (HSCs) are self-renewing cells. Some daughter cells remain HSCs so that the pool does not deplete, whereas a small population of HSC precursors gives rise to differentiated progeny cell lineages that become progressively committed toward a single cell type. For example, erythroid lineage will differentiate into the mature erythrocyte. A simultaneous expansion in the number of progeny cells occurs at each step of differentiation.

The lineage relationships among differentiating progeny of hematopoietic precursor cells have been established with great certainty. All of the intermediate cell types from multipotential hematopoietic progenitor stem cells to mature progeny cells have been characterized. The characterization includes specific cell surface markers to identify different cell types.

An early stem cell precursor, called the common hemangioblast, is the common progenitor for both hematopoietic and endothelial cell populations. This has been shown experimentally in both zebrafish and mice. The precursor to the common hemangioblast is thought to arise from early mesoderm cells that express the marker Brachyury (T), which then initiates the expression of the transmembrane tyrosine kinase receptor FlK-1, marking these cells for eventual contribution to the hematopoietic lineages. In the mouse, subsequent expression of the marker SCL signals the establishment of the common hemangioblast lineage that will give rise to both the hematopoietic and endothelial lineages. Expression of the transcription factor GATA-1 in the hemangioblast descendents signals the commitment of subsequent progeny toward the hematopoiesis pathway.

The committed (but still multipotential) HSC then gives rise to two major progenitor cell lines: the common myeloid progenitor (CMP) and the common lymphoid progenitor (CLP) ( Fig. 12.1 ). The CLP gives rise eventually to mature B cells, T cells, NK cells, and lymphoid dendritic cells. The CMP gives rise to further intermediate precursor populations: the megakaryocytic/erythrocytic progenitors (MEPs) and the common granulocyte myeloid precursor (CGMP). The CGMP gives rise to mature basophils, eosinophils, neutrophils, macrophages, myeloid dendritic cells, and mast cells.

The MEPs can differentiate into two cell lineages, either megakaryoblasts (MKP) or the committed erythropoietic progenitor (see Fig. 12.1 ). Megakaryoblasts eventually differentiate into thrombocytes or platelets, while the committed erythropoietic progenitor, now unipotential, follows a series of well-described differentiation steps that eventually give rise to mature red cells.

1.2

Erythropoiesis

During erythropoiesis, gene expression microarray profiling studies have shown that expression of genes that are not specific for the erythroid lineage is restricted in a progressive manner as progenitor cells differentiate from the HSCs stage to the mature red cell. A key cell fate decision is made by MEPs either to become megakaryoblasts or committed erythrocyte progenitors. The erythrocyte progenitor is committed to becoming an erythrocyte, and it undergoes a series of expansion and differentiation steps on its way to becoming a mature erythrocyte.

The first truly committed erythrocyte progenitor is a cell lineage called the burst-forming unit-erythroid (BFU-e). The BFU-e has been functionally defined in classic colony-formation assays as a cell that gives rise to a burst of approximately 500 mature red blood cells in 6–10 days when grown in erythropoietin (EPO) supplemented semisolid medium. A direct descendent of the BFU-e is the later-stage colony-forming unit-erythroid (CFU-e), a more mature cell that gives rise to about 8–32 red cells in 2–3 days in culture with EPO. The CFU-e differentiates into the classic erythroblasts: proerythroblasts, basophilic erythroblasts, polychromic (or polychromatophilic) erythroblasts, and orthochromic erythroblasts (see Fig. 12.1 ). The next stage in differentiation is the reticulocyte (also known as the polychromatic erythrocyte), which finally gives rise to the mature enucleated erythrocyte. Overall, approximately 200 billion erythrocytes are newly generated each day, equal to the number of erythrocytes that become senescent.