Biology Reference
In-Depth Information
number of adhesion molecules, including integrins, intercellular adhesion mol-
ecules (ICAM), and selectins, are expressed on the surface of hematopoietic
cells, their density changing as the cells mature. Adhesive interactions between
the cells and the extracellular matrix govern retention of the precursors within
the bone marrow and may have a role in stem cell homing after bone marrow
transplant [6, 7].
Hematopoietic stem cells respond to stem cell factor (SCF), a cytokine also
referred to as Kit ligand or Steel factor. The SCF receptor (SCFR or c-kit) is a
member of the superfamily of tyrosine kinase receptors; upon ligand binding,
autophosphorylation of the cytoplasmic region of the receptor initiates an intra-
cellular signal through the SH-2 recognition domains of the adaptor protein
complex Grb2/Sos, followed by activation of Ras. The message continues
through the MAP kinases and the early response genes, resulting in the activa-
tion of genes encoding the cyclins, notably the D cyclins and the cyclin-de-
pendent kinases (CDK) 4/6, to stimulate G1 progression and cell proliferation
[8]. Amplification of the SCFR pathway is dependent on stimulation by a net-
work of the early-acting cytokines, e.g., interleukins (IL-3, IL-6, and IL-9),
granulocyte colony-stimulating factor (G-CSF), and granulocyte-macrophage
colony-stimulating factor (GM-CSF), secreted by the local macrophages, mono-
cytes, and lymphocytes [7]. After development of CFU, the erythroid line pro-
ceeds through the shared CFU-GEMM (granulocyte, erythrocyte, macrophage,
megakaryocyte) precursor. The selection of lineage from this nodal point is
probably random, but may be influenced by physiologic requirements.
The erythroid-committed units of CFU-GEMM proceed through the devel-
opmental stages shown in Figure 1. The nature of the early red cell progeni-
tors, erythroid burst-forming unit (BFU-E) and erythroid colony-forming unit
(CFU-E), has been determined by
in vitro
studies of the cells grown in methyl-
cellulose. In culture, BFU-E give rise to large multiclustered “burst” colonies
of up to 30,000 cells. Morphologically, they possess the fine nuclear chro-
matin, nucleoli,and abundant cytoplasm of a blast cell. They proliferate under
the stimulus of IL-3, IL-9, GM-CSF, plus insulin-like growth factor (IGF-1).
The early BFU-E have few erythropoietin receptors (EPOR) and, therefore,
respond minimally to erythropoetin (EPO) [9]. As these cells mature, larger
numbers of EPOR are expressed and the late BFU-E become EPO responsive.
In vitro,
their CFU-E progeny generate single small colonies of 10 to 50 cells
expressing many EPOR; these cells respond strongly to EPO. EPO both stim-
ulates growth and prevents apoptosis [9];
in vitro,
cells deprived of EPO fail to
replicate and undergo apoptotic death within a few hours.
At the CFU-E phase of development, cytoskeletal proteins begin to assem-
ble and definitive membrane components appear, including red cell antigens
and the surface adhesion molecules. Interaction of the adhesion molecules
(ICAM)-1 and
α
4
β
1
integrins with the extracellular matrix serves to retain the
precursor cells within the bone marrow during proliferation and maturation.
With the loss of these adhesive proteins, the reticulocytes and red cells are free
to exit the bone marrow [7].
