Haematopoiesis

Simple diagram that shows the development of different blood cells from haematopoietic stem
cell to mature cells

Haematopoiesis (from Ancient Greek: αἷμα, "blood"; ποιεῖν "to make") (or hematopoiesis in the
United States; sometimes also haemopoiesis or hemopoiesis) is the formation of blood cellular
components. All cellular blood components are derived from haematopoietic stem cells. In a
healthy adult person, approximately 1011–1012 new blood cells are produced daily in order to
maintain steady state levels in the peripheral circulation.[1][2]

Contents
 1 Haematopoietic stem cells (HSCs)
 2 Lineages
 3 Locations
o 3.1 Extramedullary
o 3.2 Other vertebrates
 4 Maturation
o 4.1 Determination
o 4.2 Haematopoietic growth factors
o 4.3 Transcription factors
o 4.4 The myeloid-based model

Haematopoietic stem cells (HSCs)
Haematopoietic stem cells (HSCs) reside in the medulla of the bone (bone marrow) and have the
unique ability to give rise to all of the different mature blood cell types. HSCs are self renewing:
when they proliferate, at least some of their daughter cells remain as HSCs, so the pool of stem
cells does not become depleted. The other daughters of HSCs (myeloid and lymphoid progenitor
cells), however can each commit to any of the alternative differentiation pathways that lead to
the production of one or more specific types of blood cells, but cannot self-renew. This is one of
the vital processes in the body.

Lineages

Comprehensive diagram that shows the development of different blood cells from
haematopoietic stem cell to mature cells

All blood cells are divided into three lineages.

 Erythroid cells are the oxygen carrying red blood cells. Both reticulocytes and
erythrocytes are functional and are released into the blood. In fact, a reticulocyte count
estimates the rate of erythropoiesis.
 Lymphocytes are the cornerstone of the adaptive immune system. They are derived from
common lymphoid progenitors. The lymphoid lineage is primarily composed of T-cells
and B-cells (types of white blood cells). This is lymphopoiesis.
 Myelocytes, which include granulocytes, megakaryocytes and macrophages and are
derived from common myeloid progenitors, are involved in such diverse roles as innate
immunity, adaptive immunity, and blood clotting. This is myelopoiesis.

Granulopoiesis (or granulocytopoiesis) is haematopoiesis of granulocytes.

Megakaryocytopoiesis is haematopoiesis of megakaryocytes.

Locations
In developing embryos, blood formation occurs in aggregates of blood cells in the yolk sac,
called blood islands. As development progresses, blood formation occurs in the spleen, liver and
lymph nodes. When bone marrow develops, it eventually assumes the task of forming most of
the blood cells for the entire organism. However, maturation, activation, and some proliferation
of lymphoid cells occurs in secondary lymphoid organs (spleen, thymus, and lymph nodes). In
children, haematopoiesis occurs in the marrow of the long bones such as the femur and tibia. In
adults, it occurs mainly in the pelvis, cranium, vertebrae, and sternum.

Extramedullary

In some cases, the liver, thymus, and spleen may resume their haematopoietic function, if
necessary. This is called extramedullary haematopoiesis. It may cause these organs to increase in
size substantially. During fetal development, since bones and thus the bone marrow, develop
later, the liver functions as the main haematopoetic organ. Therefore, the liver is enlarged during
development.

Other vertebrates

In some vertebrates, haematopoiesis can occur wherever there is a loose stroma of connective
tissue and slow blood supply, such as the gut, spleen, kidney or ovaries.

Maturation
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. 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

Determination

Cell determination appears to be dictated by the location of differentiation.[citation needed] For

instance, the thymus provides an ideal environment for thymocytes to differentiate into a variety
of different functional T cells. 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. This is the
classical way of describing haematopoiesis. In fact, however, it is not really true. The ability of
the bone marrow to regulate the quantity of different cell types to be produced is more accurately
explained by a stochastic theory: Undifferentiated blood cells are determined to specific cell
types by randomness. The haematopoietic microenvironment prevails upon some of the cells to
survive and some, on the other hand, to perform apoptosis and die. By regulating this balance
between different cell types, the bone marrow can alter the quantity of different cells to
ultimately be produced.
Haematopoietic growth factors

Diagram including some of the important cytokines that determine which type of blood cell will
be created.[3] SCF= Stem Cell Factor Tpo= Thrombopoietin IL= Interleukin GM-CSF=
Granulocyte Macrophage-colony stimulating factor Epo= Erythropoietin M-CSF= Macrophage-
colony stimulating factor G-CSF= Granulocyte-colony stimulating factor SDF-1= Stromal cell-
derived factor-1 FLT-3 ligand= FMS-like tyrosine kinase 3 ligand TNF-a = Tumour necrosis
factor-alpha TGFβ = Transforming growth factor beta [4]

Red and white blood cell production is regulated with great precision in healthy humans, and the
production of granulocytes is rapidly increased during infection. The proliferation and self-
renewal of these cells depend on stem cell factor (SCF). Glycoprotein growth factors regulate the
proliferation and maturation of the cells that enter the blood from the marrow, and cause cells in
one or more committed cell lines to proliferate and mature. Three more factors that stimulate the
production of committed stem cells are called colony-stimulating factors (CSFs) and include
granulocyte-macrophage CSF (GM-CSF), granulocyte CSF (G-CSF) and macrophage CSF (M-
CSF). These stimulate much 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. [3] On the other
hand, thrombopoietin makes myeloid progenitor cells differentiate to megakaryocytes
(thrombocyte-forming cells).[3] Examples of cytokines and the blood cells they give rise to, is
shown in the picture to the right.

Transcription factors
Growth factors initiate signal transduction pathways, altering transcription factors, that, in turn
activate genes that determine the differentiation of blood cells.

The early committed progenitors express low levels of transcription factors that may commit
them to discrete cell lineages. Which cell lineage is selected for differentiation may depend both
on chance and on the external signals received by progenitor cells. Several transcription factors
have been isolated that regulate differentiation along the major cell lineages. For instance, PU.1
commits cells to the myeloid lineage whereas GATA-1 has an essential role in erythropoietic and
megakaryocytic differentiation. The Ikaros, Aiolos and Helios transcription factors play a major
role in lymphoid development.[5]

The myeloid-based model

For a decade now, the evidence is growing that HSC maturation follows a myeloid-based model
instead of the 'classical' schoolbook dichotomy model. In the latter model, the HSC first
generates a common myeloid-erythroid progenitor (CMEP) and a common lymphoid progenitor
(CLP). The CLP produces only T or B cells. The myeloid-based model postulates that HSCs first
diverge into the CMEP and a common myelo-lymphoid progenitor (CMLP), which generates T
and B cell progenitors through a bipotential myeloid-T progenitor and a myeloid-B progenitor
stage. The main difference is that in this new model, all erythroid, T and B lineage branches
retain the potential to generate myeloid cells (even after the segregation of T and B cell
lineages). The model proposes the idea of erythroid, T and B cells as specialized types of a
prototypic myeloid HSC. Read more in Kawamoto et al. 2010.[6]