The Questions of Developmental Biology

Blood and lymphocyte lineages.
Figure 15.21 summarizes the development of the blood and lymph cells and the paracrine
factors involved in this process. The first pluripotential hematopoietic stem cell is the CFU-M,L.
The development of this cell type appears to be dependent on the transcription factor SCL. Mice
lacking this protein die from the absence of all blood and lymphocyte lineages. SCL may specify
the ventral mesoderm to a blood cell fate, or it may enable the formation or maintenance of the
CFU-M,L cells (Porcher et al. 1996; Robb et al. 1996). The CFU-M,L give rise to the CFU-S
(blood cells) and the several lymphocytic stem cell types. The CFU-S is also pluripotent because
its progeny, too, can differentiate into numerous cell types. The immediate progeny of the CFU-S,
however, are lineage-restricted stem cells. Each can produce only one type of cell in addition to
renewing itself. The BFU-E (burst-forming unit, erythroid), for instance, is a lineage-restricted
stem cell formed from the CFU-S, and it can form only one cell type in addition to itself. That
cell type is the CFU-E (colony-forming unit, erythroid), which is capable of responding to the
hormone erythropoietin to produce the first recognizable differentiated member of the
erythrocyte lineage, the proerythroblast, a red blood cell precursor. Erythropoietin is a
glycoprotein that rapidly induces the synthesis of the mRNA for globin (Krantz and Goldwasser
1965). It is produced predominantly in the kidney, and its synthesis is responsive to
environmental conditions. If the level of blood oxygen falls, erythropoietin production is
increased, leading to the production of more red blood cells. As the proerythroblast matures, it
becomes an erythroblast, synthesizing enormous amounts of hemoglobin. Eventually, the
mammalian erythroblast expels its nucleus, becoming a reticulocyte. Reticulocytes can no longer
synthesize globin mRNA, but they can still translate existing messages into globin. The final
stage of differentiation is the erythrocyte, or mature red blood cell. Here, no division, RNA
synthesis, or protein synthesis takes place. The DNA of the erythrocyte condenses and makes no
further messages. Amphibians, fish, and birds retain the functionless nucleus; mammals extrude it
from the cell. The cell leaves the bone marrow and delivers oxygen to the body tissues.
Similarly, there are lineage-restricted stem cells that give rise to platelets, to granulocytes
(neutrophils, basophils, and eosinophils), and to macrophages.
Some hematopoietic growth factors (such as IL-3) stimulate the division and maturation
of the early stem cells, thus increasing the numbers of all blood cell types. Other factors (such as
erythropoietin) are specific for certain cell lineages only. A cell's ability to respond to these
factors is dependent upon the presence of receptors for the factors on its surface. The number of
these receptors is quite low. There are only about 700 receptors for erythropoietin on a CFU-E,
and most other progenitor cells have similar low numbers of growth factor receptors. The
exception is the receptor for macrophage colony-stimulating factor M-CSF, also known as
CSF-1 which can number up to 73,000 per cell on certain progenitor cells.
Hematopoietic inductive microenvironments.
Different paracrine factors are important in causing hematopoietic stem cells to
differentiate along particular pathways (see Figure 15.21). The paracrine factors involved in
blood cell and lymphocyte formation are called cytokines. Cytokines can be made by several cell
types, but they are collected and concentrated by the extracellular matrix of the stromal
(mesenchymal) cells at the sites of hematopoiesis (Hunt et al. 1987; Whitlock et al. 1987). For
instance, granulocyte-macrophage colony-stimulating factor (GM-CSF) and the multilineage
growth factor IL-3 both bind to the heparan sulfate glycosaminoglycan of the bone marrow
stroma (Gordon et al. 1987; Roberts et al. 1988). The extracellular matrix is then able to present
these factors to the stem cells in concentrations high enough to bind to their receptors.
The developmental path taken by the descendant of a pluripotential stem cell depends on
which growth factors it meets, and is therefore determined by the stromal cells. Wolf and Trentin
(1968) demonstrated that short-range interactions between stromal cells and stem cells determine