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Hematopoiesis (from Greek haima for blood and poiein, to make) is the dynamic and
complex developmental process of the formation of new blood cells. Understanding the
biology of hematopoietic stem cells as well as hematopoiesis is important to developing
improved treatments for hematologic malignancies, congenital disorders, chemotherapyrelated cytopenias, and blood and marrow transplants.
I. Introduction
Each day the human body produces billions of new white blood cells, red blood cells, and
platelets to replace blood cells lost to normal cell turnover processes as well as to illness
or trauma. A variety of homeostatic mechanisms allow blood cell production to respond
quickly to stresses such as bleeding or infection and then return to normal levels when the
stress is resolved. The highly orchestrated process of blood cell production and
homeostasis is termed hematopoiesis.
An understanding of the principal mechanisms in hematopoiesis, as well as our
current understanding of the processes central to hematopoiesis, is important to the
practice of oncology for a variety of reasons. Disorders of hematopoiesis underlie a
number of hematologic malignancies and other disorders such as leukemia, aplastic
anemia, lymphoma, myelodysplasia, myeloproliferative disorders, and inborn errors of
metabolism. Chemotherapy-induced cytopenia is one of the primary causes of morbidity
and mortality in the treatment of cancer.
th
3 to 7 month
spleen
th
7 month
Birth
Birth to maturity
Adult
In healthy persons, the marrow is for practical purposes the only site of
hematopoiesis. However, during periods of hematopoietic stress, the liver and spleen may
revert to their fetal role and produce blood cells in the adult. Examples of this event may
be seen, for example, when the marrow is replaced by metastatic breast cancer or by
fibrosis.
blood. This elegant process, which generally is restricted to the bone marrow, is
referred to as hematopoiesis.
The very first step in hematopoietic differentiation involves a commitment of the
stem cell to either one of two large pathways, myeloid or lymphoid. Subsequently,
progeny of cells committed to each of theses two pathways may become obligated to
specific sublines of development. After becoming committed to a specific pathway, or
lineage, the cells are referred to as committed progenitor cells. These cells have lost the
capacity for self-renewal and are committed to a given cell lineage.
Hematopoietic ontogeny can be represented by a tree whose trunk divides early
into two large branches and some of whose smaller branches divide many times.
V. Erythropoiesis
As the cells are maturing In the erythrocytic series, the cells are usually getting smaller,
the nucleus is becoming smaller and more condensed and is eventually lost, and the
cytoplasm is becoming more pink rather than blue.
VI. Granulopoiesis
Unipotent stem cell: not shown, cannot be distinguished from other unipotent
stem cells histologically
Myeloblast: large cell with blue-staining cytoplasm; large nucleus; often as in
this example, a clear area near the nucleus can be seen - this is where the rather
large Golgi is located
Promyelocyte: example not shown; still a rather large cell with azurophilic (not
specifically stained) granules
Myelocyte: example not shown; overall cell still rather large; nucleus still round
without indentation; granules staining appropriately for the series, i.e., pink for
eosinophilic, blue for basophilic, neutral for neutrophilic
Metamyelocyte: cell is about the size of a mature granulocyte; nucleus with
slight indentation; granules present that stain appropriately for the series, i.e., pink
for eosinophilic, blue for basophilic, neutral for neutrophilic
Band cell: cell is about the size of a mature granulocyte; nucleus with definite
indentation - looks like a horseshoe; prominent granules that stain appropriately
for the series
Mature (segmented) granulocyte: cell is mature and looks like normal, mature
granulocytes in the blood with lobed nucleus and prominent granules that stain
appropriately for the series.
VII. Thrombopoiesis
VIII. Lymphoiesis
The lymphoid pathway subdivides into the B cell pathway; the T cell pathway; and the
"null" cell, or "non-B, non-T' cell pathway.
B cell development to the stage of the mature B lymphocyte is completed within
the bone marrow. Further differentiation into Plasma Cells or memory B cells
does not occur until the mature (but nave) B lymphocyte encounters specific
antigen.
T cell development to the stage of the precursor T lymphocyte occurs within the
bone marrow. The precursor T lymphocytes (otherwise known as pre-Ts) then
must go to the thymus to complete maturation. When mature T lymphocytes leave
the thymus, they leave as mature (but nave ) Tc (T cytotoxic lymphocytes) or Th
(T helper lymphocytes). Further differentiation does not occur until the mature T
cells encounter antigen (presented to the T cell in association with MHC proteins).
The complex orchestration of hematopoiesis through which the elaborate array of blood
cells described above is produced requires three physiologic components, each of which
is essential. These are:
the stem cell pool itself (described above);
the hematopoietic inductive microenvironment, which is made up of the
bone marrow stroma and vasculature; and
hematopoietic cytokines, which are the hormones that regulate
hematopoiesis through both endocrine and paracrine mechanisms
X. Hematopoietic Cytokines
The hormones that regulate blood cell production are called hematopoietic cytokines.
Most of them were discovered starting in the mid 1960's. These growth factors are
present at extremely low concentrations and biological activity at concentrations as low
as 10-12 M. Some of the natural hormones were laboriously biochemically purified, and
starting in the mid 1980's, various laboratories began to clone the genes that encoded
many of these glycoproteins. As a consequence, it became possible to express synthetic
hematopoietic cytokines as recombinant proteins. Now, more than 20 of these hormones
have been cloned and sequenced, and more are emerging every day.
CSFs- act in a stepwise manner inducing proper maturation.
IL-3 [multi-CSF] acts early, possibly even at the level of the pluripotent stem cell,
to induce formation of the nonlymphoid cells (erythrocytes, monocytes,
granulocytes[neutrophils, eosinophils, basophils], and megakaryocytes).
GM-CSF acts at a slightly later stage, but it also induces formation of all the
nonlymphoid blood cells.
M-CSF and G-CSF act still later to promote the formation of monocytes and
granulocytic cells, respectively.
Erythropoietin (Epo) - is mainly a differentiation factor for late determined and
differentiated progenitor cells of erythropoiesis. It determines their differentiation
and maturation into erythrocytes. In addition Epo also regulates the proliferation
of erythropoietic progenitor cells . The Epo sensitivity progressively increases
with differentiation of immature progenitor cells (see: BFU-E , CFU-E . Epo has
not been shown to act on pluripotent hematopoietic stem cells
IL-4 - stimulates B progenitors, mast progenitors, and basophil progenitors
IL-5 - stimulates eosinophil progenitor
IL-6 - stimulates the myeloid stem cell
IL-7 - induces the differentiation of lymphoid progenitor into B progenitor and T
progenitor
IL-8 - stimulates the neutrophil progenitor
IL-9 - stimulates mast cell growth
Committment of a progenitor cell is associated with the expression on the cell
membrane of membrane receptors that are specific for particular cytokines.
Hematopoiesis is a continuous process throughout adulthood. Production of mature
blood cells equals their loss. Estimated that the average human must produce 3.7X1011
blood cells per day. This process is regulated by complex mechanisms.
Cell division and differentiation during hematopoiesis are balanced by apoptosis - there
must by maintenance of a steady state.
During apoptosis you see:
a decrease in cell volume
modification of the cytoskeleton with pronounced membrane blebbing
condensation of chromatin
degradation of DNA into oligonulceosomal fragments
shedding of apoptotic bodies