Part VI. HEMATOLOGICAL DISORDERS

Hematopoiesis is a finely regulated process of successive differentiation of progenitor cells leading to the formation of mature blood cells of all 8 lineages.

• Myeloid:
  • erythrocytes;
  • basophilic, eosinophilic and neutrophilic granulocytes;
  • megakaryocytes;
  • monocytes — macrophages;
• lymphoid:
  • Т-lymphocytes;
  • В-lymphocytes.

Hematopoietic Organs

Hematopoietic cells develop in organs of hematopoiesis, that are classified as:

• embryonic (yolk sac, embryonic liver, spleen and bone marrow);
• mature (bone marrow, spleen, thymus, lymph nodes and Peyer’s patches).

Bone marrow hemopoiesis occurs in cavities of all tubular and flat bones, in the space between the sinuses — the so-called hematopoietic (stromal) microenvironment. Microenvironment cells include the following types:

• endothelial;
• adventitious;
• reticular (bone marrow fibroblasts);
• macrophages;
• adipocytes;
• osteoclasts;
• osteocytes.

The extracellular matrix consists of a range of insoluble proteins (glycosaminoglycans, proteoglycans, fibronectin, GP), collagen and elastin fibers forming a mesh-like structure, where strands of hematopoietic cells and stromal bone substance are located. The ability of hematopoietic cells to recognize stromal cells and be distributed in stroma (homing) is caused by cell adhesion molecules, integrins and direct cell-to-cell contacts. This feature of the cells becomes apparent after bone marrow transplant: 85% of intravenously administered cells enter bone marrow, the weight of that is 6% of body weight. The remaining 15% are distributed between liver, lungs, spleen and other organs.

The germline hematopoietic cells are localized in the bone marrow. Т- and В-lymphocyte precursors also develop in bone marrow; however, their final differentiation occurs in the thymus (Т-lymphocytes) and spleen, lymph nodes and Peyer’s patches (В-lymphocytes).

The spleen morphologically consists of two compartments: red and white pulp. In the red pulp, erythrocytes are deposited and destroyed. Most macrophages of the red pulp phagocytes destroyed erythrocytes and iron pigments. The white pulp formed by arteries and their surrounding sheaths of lymphoid tissue is mainly populated with T-lymphocytes. В-lymphocyte clusters are located on the periphery of periarterial areas. After antigenic stimulation, primary follicles develop into secondary that have germinal centers. In these centers, В-lymphocytes and plasma cells develop.

Thymus is the central and highly specialized lymphopoietic organ, in that maturation and clonal selection of T-lymphocytes, as well as removal of autoreactive clones take place. Т-lymphocyte precursors enter the cortex of the thymus from the bone marrow. Cortex thymocytes are characterized by high proliferation rate; however, most of them die, and a part of their population acquires specific T-helpers and T-suppressors markers and migrates through the thymus medulla to the secondary lymphoid organs (spleen, lymph nodes).

With aging, thymus involution occurs; however, it is never completely replaced by adipose tissue, and production of humoral factors is continued. Lymphopoietic function is then taken over by Langerhans cells in the skin, and mesenteric lymphoid cell clusters.

The lymph nodes are the basis of immune response development. In the sinuses of lymph nodes, macrophages capturing an antigen present it to B-lymphocytes directly implementing immune response. Subcapsular area of lymph nodes is predominantly populated by Т-lymphocytes and dendritic cells carrying a large number of class II histocompatibility molecules necessary for Т-lymphocyte activation. Medullary area is populated by more mature cells secreting ABs.

Structure and function of Peyer’s patches located along the small intestinal wall are similar to lymphoid follicles of the spleen and lymph nodes.

Schematic Representation of Hematopoiesis

The main provisions of hematopoietic scheme [absence of immortal, “self-renewing” hematopoietic stem cells (HSCs), possibility of reduction in the number of mitoses during maturation, clonal nature of hematopoiesis with clone changes, the presence of not yet identified precursors preexisting HSCs etc.] have been confirmed many times for many years. After the loss of the main property of stem cells and only stem cells alone — the ability to self-renewal, with impossibility of defining the very concept of “stemness”, the only criterion of cell affiliation to stem lineage is a proliferative potential sufficient for multi-lineage recovery of hematopoiesis after depression of proper hematopoiesis.

The time for establishing the basis of HSC molecular biology is yet to come, and it is not yet possible to make up the more clear overview of gene arrangement during hematopoietic differentiation.

There are very few amendments in the lower branches of hematopoietic tree. Apart from 8 previously known hematopoietic differentiation lineages, there were some new added:

• natural killer cells (cells involved in natural immunity including against malignant cells);
• professional antigen-presenting dendritic cells.

At present, 11–12 hematopoietic cells differentiation lineages are distinguished.

Hematopoiesis scheme (Figure 47.1) begins from the only member of the totipotent precursors department — embryonic HSC. This cell is capable of developing into a cell of any tissue of the body. Embryonic HSCs are separated from internal blastocyst mass at the stage of approximately 100–120 cells. In embryogenesis, these cells quickly move to the next differentiation stages. Embryonic HSCs are formed only in the setting of in vitro arrest of blastocyst cells maturation, e.g. when cultivated under certain conditions. Cell differentiation of germ bladder is blocked, and they are able to proliferate virtually indefinitely (>120 doublings) without differentiation, malignancy, changes in karyotype, etc. Removal of the block leads to disorderly differentiation of the embryonic HSC. Although prudent clinical use of embryonic HSC is still further, it would be expedient even now to place this precursor at the top of hematopoietic hierarchy.