As a stem cell matures it undergoes changes in
gene expression that limit the cell types that it can become and moves it closer to a specific cell type (
cellular differentiation). These changes can often be tracked by monitoring the presence of proteins on the surface of the cell. Each successive change moves the cell closer to the final cell type and further limits its potential to become a different cell type.
Cell fate determination Two models for haematopoiesis have been proposed: determinism and stochastic theory. For the stem cells and other undifferentiated blood cells in the bone marrow, the determination is generally explained by the
determinism theory of haematopoiesis, saying that colony stimulating factors and other factors of the haematopoietic microenvironment determine the cells to follow a certain path of cell differentiation. Furthermore, it was shown that if allowed to grow, this subpopulation re-established the original subpopulation of cells, supporting the theory that this is a stochastic, reversible process. Another level at which stochasticity may be important is in the process of apoptosis and self-renewal. In this case, the haematopoietic microenvironment prevails upon some of the cells to survive and some, on the other hand, to perform
apoptosis and die.
Growth factors Red and white blood cell production is regulated with great precision in healthy humans, and the production of leukocytes is rapidly increased during infection. The proliferation and self-renewal of these cells depend on growth factors. One of the key players in self-renewal and development of haematopoietic cells is
stem cell factor (SCF), which binds to the c-kit receptor on the HSC. Absence of SCF is lethal. There are other important
glycoprotein growth factors which regulate the proliferation and maturation, such as
interleukins
IL-2,
IL-3,
IL-6,
IL-7. Other factors, termed
colony-stimulating factors (CSFs), specifically stimulate the production of committed cells. Three CSFs are
granulocyte-macrophage CSF (GM-CSF),
granulocyte CSF (G-CSF) and
macrophage CSF (M-CSF). These stimulate
granulocyte formation and are active on either
progenitor cells or end product cells.
Erythropoietin is required for a myeloid progenitor cell to become an erythrocyte. On the other hand,
thrombopoietin makes myeloid progenitor cells differentiate to
megakaryocytes (
thrombocyte-forming cells).
Transcription factors Growth factors initiate
signal transduction pathways, which lead to activation of
transcription factors. Growth factors elicit different outcomes depending on the combination of factors and the cell's stage of differentiation. For example, long-term expression of
PU.1 results in myeloid commitment, and short-term induction of PU.1 activity leads to the formation of immature eosinophils. Recently, it was reported that transcription factors such as
NF-κB can be regulated by
microRNAs (e.g., miR-125b) in haematopoiesis. The first key player of differentiation from HSC to a multipotent progenitor (MPP) is transcription factor CCAAT-enhancer binding protein α (
C/EBPα). Mutations in C/EBPα are associated with
acute myeloid leukaemia. From this point, cells can either differentiate along the Erythroid-megakaryocyte lineage or lymphoid and myeloid lineage, which have common progenitor, called lymphoid-primed multipotent progenitor. There are two main transcription factors. PU.1 for Erythroid-megakaryocyte lineage and
GATA-1, which leads to a lymphoid-primed multipotent progenitor. Other transcription factors include Ikaros (
B cell development), and
Gfi1 (promotes
Th2 development and inhibits Th1) or
IRF8 (
basophils and
mast cells). Significantly, certain factors elicit different responses at different stages in the haematopoiesis. For example, CEBPα in neutrophil development or
PU.1 in monocytes and dendritic cell development. Processes are not unidirectional: differentiated cells may regain attributes of progenitor cells. Surprisingly, pax5 conditional knock out mice allowed peripheral mature B cells to de-differentiate to early bone marrow progenitors. These findings show that transcription factors act as caretakers of differentiation level and not only as initiators.
Mutations in transcription factors are tightly connected to blood cancers, as
acute myeloid leukemia (AML) or
acute lymphoblastic leukemia (ALL). For example, Ikaros is known to be regulator of numerous biological events. Mice with no Ikaros lack
B cells,
Natural killer and
T cells. Ikaros has six
zinc fingers domains, four are conserved
DNA-binding domain and two are for
dimerization. Very important finding is, that different zinc fingers are involved in binding to different place in DNA and this is the reason for pleiotropic effect of Ikaros and different involvement in cancer, but mainly are mutations associated with
BCR-Abl patients and it is bad prognostic marker. == Other animals ==