Blood Tissue Histology, Hematopoiesis, and Blood Cells

Blood Tissue and Free Cell Populations

Preliminary Note: Free cell populations consist of cells that are not associated to form a coherent, topographically determined, and relatively well-circumscribed structure. They are primarily grouped under blood cells (globules) and immunocompetent cells. They are also referred to as a diffuse cellular system—that is, distributed throughout the tissues of organs proper.

A common functional characteristic of all these cells is mobility. Most of these cells are located in the lymph and, especially, in the blood. They are occasionally termed immigrant cells.

Free cell populations are found in:

• Circulating tissues: Blood, lymph, cerebrospinal fluid.
• Hematopoietic tissues: Red bone marrow and lymphoid formations.
• Other tissues: Epithelial, connective, and others.

Immunocompetent cells of the immune system involved in specific defense mechanisms settle in: the hematopoietic red bone marrow, blood, lymph, and lymphoid formations.

Embryonic, Fetal, and Postnatal Hematopoiesis

Hematopoiesis occurs within hematopoietic tissues and organs. In the adult animal, there are two principal foci of hematopoietic activity: myeloid tissue, located in the red bone marrow, and lymphoid tissue, an integral component of lymphoid organs and formations.

Hematopoietic Periods

During embryonic and fetal development, three distinct periods of hematopoiesis are recognized:

1. Prehepatic (or Mesenchymal) Period: Occurs between the second and twelfth weeks of human development. Blood elements differentiate from the mesenchyme of the extraembryonic yolk sac lining, where the blood islands of Wolff and Pander are formed.
2. Hepato-Lymphoid Period: Makes its appearance around the second month of human development at the level of the liver, spleen, thymus, and lymph nodes. Elements of all blood cell series are generated. Blood cell formation here is gradually replaced from the sixth month onward by the bone marrow.
3. Medullo-Lymphoid Period: Becomes established in the bone marrow beginning in the sixth month of development. The various blood precursors appear intermingled inside the red bone marrow within:
   • A myeloid tissue reticular framework that supports connective cells of various blood series.
   • Adipocytes in varying quantities.
   • Blood sinusoids/capillaries with large, discontinuous, and sinuous endothelial lumens to release mature elements.

Hematopoietic Stem Cells and Differentiation

Competent Hematopoietic Stem Cell (Pluripotent): This is a determined mesenchymal cell capable of forming cells committed to differentiation into elements belonging to the diverse blood cell lines: erythrocytic, megakaryocytic/platelet, monocyte-granulocytic, and lymphocytic series. The progeny of the pluripotent stem cell can follow diverse differentiation alternatives. Prior to differentiation, all these stem cells exhibit a very similar appearance, rendering identification by morphological means impossible.

The classical first experiment to demonstrate the existence of pluripotent stem cells in the bone marrow consisted of:

• Animals were irradiated with lethal doses of X-rays; bone marrow from a syngeneic donor was then transfused to provide the irradiated host with new hematopoietic tissue.
• Several days later, distinct colonies of cells developed.
• Using genetic markers, it was verified that the splenic nodules were clones derived from a single founder cell: the CFU (Colony-Forming Unit), demonstrating they are true stem cells.

Committed Hematopoietic Stem Cell (Progenitor): This is a cell that has acquired the irreversible commitment to follow a single lineage of differentiation, thus becoming unipotent. This commitment is followed by a series of cell divisions that amplify the committed progenitor cells. These amplification divisions are subject to critical controls that regulate the rate of production for each lineage. Committed progenitor cells reside in the bone marrow and lymphoid organs and formations.

Hematopoietic Regulation

1. Erythropoietin (EPO): A hormone produced primarily at the renal level that stimulates erythropoiesis.
2. Hormones and Factors Analogous to Erythropoietin: Produced in response to specific systemic demands regarding various types of white blood cells or platelets. The existence of specific humoral glycoprotein factors for each precursor cell variant is established; humoral interleukins also participate actively in hematopoiesis.
3. GM-CSF (Granulocyte-Macrophage Colony-Stimulating Factor): Neutrophil granulocytes and macrophages are derived from a common committed precursor. The survival of this precursor depends upon GM-CSF. Blood concentrations of GM-CSF rise sharply following infection.
4. Other Factors: Hypothalamic, pituitary, and adrenocortical hormones; iron, cobalt, vitamin B12, and folic acid.
5. Feedback Mechanisms: Mature cellular elements in peripheral blood trigger feedback mechanisms that either stimulate or inhibit the differentiation of precursors across the diverse series within the various hematopoietic organs.

Composition and Functions of Blood

Blood Composition

• Plasma: 55%–60%
• Formed Elements (Blood Cells and Corpuscles): 40%–45%
  • Corpuscles:
    • Erythrocytes (Red Blood Cells / Hematies): 4.5–5.0 million/mm³ in females; 4.5–5.5 million/mm³ in males.
    • Thrombocytes (Platelets): 150,000–300,000/mm³.
  • White Blood Cells (Leukocytes): 5,000–7,000/mm³
    • Granulocytes: Neutrophils (band/juvenile: 1%–3%, segmented: 60%–70%), Eosinophils (1%–3%), Basophils (0.5%–1%).
    • Agranulocytes: Lymphocytes (20%–40%), Monocytes (2%–6%).

Blood Functions

• Transport of Nutrients: Carries nutrients from the intestine and chyliferous vessels to tissues; from tissues to the liver and back; and from one tissue to another.
• Respiratory Gas Exchange: Facilitates O₂ and CO₂ transport between tissues and the lungs (hematosis).
• Excretion Transport: Transports metabolic waste products from tissues to the kidneys, skin, liver, and intestine for elimination.
• Signaling Distribution: Distributes regulatory hormones and biochemical mediators.
• Immune Protection: Protects against invading microorganisms and foreign antigens.
• Homeostasis: Maintains acid-base equilibrium, water, and mineral balance.
• Thermoregulation and Hemostasis: Regulates body temperature and facilitates blood coagulation.

Erythrocyte Life Cycle: Mature Red Blood Cell

Structure and Characteristics

Erythrocytes (red blood cells or hematies) are anucleate cellular corpuscles whose primary function is the transport and release of O₂ and CO₂ (hematosis). They possess a biconcave discoid shape, which strongly favors gaseous exchange by maximizing the surface-area-to-volume ratio. Their elasticity and shape maintenance depend directly on the cytoskeleton protein network: spectrin, actin, and tropomyosin.

In humans, erythrocytes measure approximately 7.8 μm in maximum diameter, with a thickness of approximately 2.0 μm at the periphery and 1.0–1.5 μm at the center.

Internal Structure: An outer plasma membrane delimits a homogeneous, amorphous, moderately electron-dense eosinophilic cytoplasm composed essentially of hemoglobin. They lack a nucleus and organelles. Under normal physiological conditions, approximately 1% of circulating red blood cells are reticulocytes (immature red blood cells that still retain remnants of ribosomes and other organelles, which appear under the light microscope as basophilic lumps or a delicate network upon vital staining).

Half-Life, Destruction, and Erythropoiesis

Half-Life and Destruction: Once released from the bone marrow into circulating blood, the average lifespan of red blood cells is approximately 120 days. Destruction of aged, worn, and defective erythrocytes occurs fundamentally in the spleen, and to a lesser degree in the liver and bone marrow itself. Macrophages phagocytose and degrade these cells, recycling iron and globin amino acids in a process called erythrocatheteresis (hemocateresis).

Erythropoiesis: Erythrocyte production takes place in the red bone marrow through erythropoiesis. It begins with an erythropoietic progenitor cell that differentiates sequentially through the following cell stages:

1. Pronormoblast (Proerythroblast)
2. Basophilic erythroblast
3. Polychromatophilic erythroblast
4. Normoblast (Orthochromatophilic erythroblast)
5. Reticulocyte
6. Mature erythrocyte

As cells of the erythroid series differentiate and mature, they progressively decrease in total volume, condense their nuclear chromatin until nucleus expulsion at the late normoblast stage, increase hemoglobin synthesis, and lose their cytoplasmic organelles.

Thrombocyte Life Cycle: Mature Platelets

Structure and Characteristics

Thrombocytes (platelets) are cytoplasmic cell fragments involved in hemostasis and blood clotting. Their morphology is oval, elongated, or discoid, with dimensions typically ranging between 2 and 3 μm.

Ultrastructure: A bounding trilaminar plasma membrane encloses a corpuscular compartment that exhibits a peripheral clear halo under light microscopy. Structurally, two distinct zones are recognized:

• Hyalomere: The peripheral, pale-staining zone containing contractile microfilaments and a marginal band of microtubules.
• Granulomere: The central granular zone containing alpha (α), beta (β), and delta (δ) membrane-delimited granules, hydrolytic enzymes, peroxidases, platelet factors 3 and 4, serotonin, calcium ions, ATP, ADP, catecholamines, as well as sparse ribosomes and mitochondria.

Half-Life, Destruction, and Thrombopoiesis

Half-Life and Destruction: The average circulating lifespan of platelets once they leave the bone marrow is 4 to 12 days. Senescent, defective, or worn-out platelets are removed and destroyed primarily by macrophages in the spleen, as well as in the liver and bone marrow, through a process designated as thrombocateresis.

Thrombopoiesis: Platelet production occurs in the red bone marrow through thrombopoiesis, arising through fragmentation of mature megakaryocytes derived from committed hematopoietic stem cells.