Notes by dott. Claudio Italiano
There are three main types of stem cell:
- embryonic stem cells.
- adult stem cells.
- induced pluripotent stem cells.
In hematology, stem cells are used in the process of marrow transplantation, for the treatment of oncological processes of hematological relevance, and are collected by special procedures. Here we discuss this type of cells.
Hematopoiesis is the process that presides over the formation and development of the various cellular elements of the blood. The constituents of peripheral blood derive from a complex ontogeny and under tight regulation. The pluripotent stem cell hemopoietic cell is conserved by self-renewal and also undergoes differentiation in multiple cell lines in order to generate the appropriate amounts and types of cells within the bloodstream.
The hematopoietic system is unique in that it is constantly subject to this complete cycle of maturation through which a stem cell develops into various highly specialized terminal cells, which have existences of different duration and are present in different quantities. Bone marrow must have the ability to generate these elements to compensate for the fast normal turnover of haematopoietic cells resulting from aging, use and migration into tissue spaces. Moreover, this system must have a reserve capacity to produce a greater number of cells in response to the unusual requests that follow the onset of bleeding, infections or other stressful situations. Understanding the repetitive cycle of cellular ontogeny and self-renewal that addresses these challenges provides a thorough understanding of the normal and pathological mechanisms of hematology.
Hematopoiesis begins in the embryo sac, where the first erythroblasts form the
first cells containing hemoglobin in the bloodstream. After 6 weeks of budding,
the fetal liver begins to produce primitive lymphocyte cells, megakaryocytes and
erythroblasts, while the spleen is a secondary site of erythropoiesis. The
hematopoiesis then moves to its long-term definitive site, the bone marrow,
which is the main site for hematopoiesis throughout the life cycle of the normal
host. At the dawn of life, all fetal bones contain this regenerative marrow,
which is progressively replaced with the passing of the years. Adult bone marrow
is found only in the axial skeleton (vertebrae, pelvis, ribs) and in the
proximal extremities of the femur and humerus. As a result, bone marrow samples,
which are indispensable for many haematological diagnoses, are usually taken
from the iliac crest or the sternum. In the pathological conditions that stress
the capacity of the medullary space, as occurs in diseases that cause bone
marrow fibrosis (myeloproliferative diseases) or in severe hereditary hemolytic
anemia (a-thalassemia), a recovery of the extramedullary hematopoiesis in places
of fetal hematopoiesis, especially in the spleen.
All mature haematopoietic cells are thought to derive from a small population of pluripotent stem cells. These cells, which make up less than 1% of the total cells of the bone marrow, do not possess distinctive morphological signs and are defined above all by their unique functional properties. Stem cells have two distinctive characteristics. The first concerns their remarkable ability to recover and reproduce, continuously repopulating an immense quantity of granulocytes, lymphocytes and erythrocytes throughout life. The demand for a continuous fluctuating supply of blood cells requires a hematopoietic system capable of producing a large number of special cells in a short time. For example, a particularly violent infection by microorganisms triggers the release of neutrophils, while hypoxia or acute hemorrhage require an increased production of red blood cells.
The second characteristic concerns the fact that
stem cells form a self-regenerating cell population while keeping its number
unchanged and at the same time providing a continuous supply of progenitor cells
of many different cell lines. In spite of their vast proliferative potential,
most of the stem cells, under normal conditions, are paradoxically resting,
while only some of them expand or differ at a given moment. However, their
ability to proliferate is extraordinary. Studies conducted on mice irradiated
with lethal doses have demonstrated the ability of some transplanted cells (called
CFU-S cells [colony-forming unit-spleen, a splenic origin which forms colonies])
to regenerate the hematopoiesis of the various cell lines . Signals that
regulate the differentiation of pluripotent stem cells into committed progenitor
cells are not known. The data suggest that the first step towards a lineage
commitment is a stochastic (random) event; furthermore, it is hypothesized that
the subsequent stages of maturation will occur under the influence of growth
factors, called cytokines. Cytokines act on different cells by specific
receptors. The activation of these receptors induces mechanisms of transduction
of signals that lead to the transcription of genes and finally to the
proliferation and differentiation of cells. It has also been shown that these
growth factors act as survival factors for developing hemopoietic cells,
preventing apoptosis (programmed cell death). This process occurs in the
cellular environment of the bone marrow; It is also well known that
hematopoiesis depends in part on non-haematopoietic cells (fibroblasts,
endothelial cells, osteoblasts, adipocytes that make up the bone marrow
microenvironment.) Stem cell biology is also regulated by locally produced
haematopoietic and interactions of bonds of cell surface that occur between the
primitive cells and the surrounding parenchyma.
Hematopoiesis proceeds along a strictly regulated hierarchy. As more primitive cells mature under the influence of specific cytokines, various cell divisions occur, transforming them into progenitor cells committed to a single lineage. At the same time they lose their ability to self-renew. From the morphological side, these non-specific cells similar to hemocyte-blasts are transformed into cells that can be identified by their color, shape and granular and nuclear content. On the functional side, they acquire characteristic surface cell receptors and the ability to respond to specific signals. Granulocytes and erythroid cells undergoing maturation undergo several other cell divisions in the bone marrow, while lymphocytes reach the thymus and lymph nodes to complete their development. Megakaryocytes stop their cell division, but nuclear multiplication continues. Finally, these cells are released from the bone marrow in the form of erythrocytes, mast cells, granulocytes, monocytes, eosinophils, macrophages and platelets, all fully functioning elements.
The pluripotent stem cell can not be distinguished from the morphological side,
but is better identified by its expression of the cell differentiation antigen,
the CD34, and by its ability to generate in vitro pluripotent colonies. Under
the influence of interleukin-1 (IL-1), IL-3, IL-6 and a specific factor for the
stem cell (ligand c-kit or steel factor), this cell continues its maturation
towards a cell progenitor of a myeloid lineage (CFU-granulocytes / erythrocytes
/ macrophages / megakaryocytes [CFU-GEMM]) or towards a parent cell of a
lymphoid lineage. In the presence of a stimulating factor for macrophage
granulocyte (GM-CSF) and IL-3 granulocyte colonies, the myeloid primitive cell
is further differentiated into daughter cells of its particular lineage. On the
other hand, the lymphopoietic mother cell will become a pre-B cell or a
pro-thymocyte (pre-T cell) and will abandon the osSeo marrow for further
maturation.
Hematology