How RBC and WBC are formed from hematopoiesis stem cells?

Hematopoiesis is the formation and development of red blood cell and white blood cell from a type of cell called hematopoiesis stem cell (HSC).

By the third month of gestation,

HSGs migrate from the yolk sac to the fetal liver and colonize in the spleen.Liver and spleen play a significant role in hematopoiesis from  3rd to 7th months of gestation( both have no role in hematopoiesis after birth).

After this,

The differentiation of hematopoietic stem cell in the bone marrow becomes the major factor in hematopoiesis.

The study of hematopoietic stem cells is difficult for two reasons:-

    • They are scarce, normally fewer than on HSC per 5X10cells in the bone marrow.
    • They are difficult to grow in vitro.

Initially in hematopoiesis,

A multipotent stem cell differentiates in one of the two pathways given below:-

  1. Lymphoid progenitor cell.
  2. Myeloid progenitor cell.

Progenitor cells have lost the capacity for self-renewal and are committed to a particular cell lineage.

Lymphoid progenitor cells give rise to B-cells, T-cells, Natural killer cells (NK cells).

Myeloid progenitor cells give rise to dendritic cells, megakaryocytes (Platelet-generating cells), erythroid progenitor, basophil progenitor, eosinophil progenitor and granulocyte-monocyte progenitor cells.

In the bone marrow,

HC and their descendants grow, differentiate, and mature on a mesh-like scaffold of stromal cells stromal cells.

Stromal cells provide hematopoietic-inducing microenvironment (HIM) for the differentiation of hematopoietic stem cell.

The stromal cells include fat cells, endothelial cells, fibroblasts, and macrophages and hematopoietic-inducing microenvironment consist of a cellular matrix and growth and differentiation-promoting factors.

Role of some transcription factor in hematopoiesis

GATA-1 is required for erythroid lineage.

GATA-2 is a transcription factor that affects multiple lineages (lymphoid, erythroid, and myeloid lineages).

Ikaros is required only for the development of cells of the lymphoid lineage.

Bmi-1 is a transcriptional repressor that is a key determinant of the ability of HSCs to self-renew.

Factors involved in Hematopoietic homeostasis

Hematopoiesis is a steady-state process in which rate of production of mature blood cells are equal to the rate at which they are lost.

Lifespan for erythrocyte – They have an average lifespan of 120 days after which macrophages destroy them in the spleen.

Lifespan for white blood cells – The lifespan ranges from one day for neutrophils, to  20-30 years for some T lymphocytes.

Programmed cell death is an essential homeostatic mechanism

Programmed cell death is an induced and ordered process in which the cell actively participates in bringing about its own demise.

The morphologic changes exhibited by cells undergoing programmed cell death is referred to as apoptosis.

The changes in apoptosis are:-

  • A pronounced decrease in cell volume.
  • Modification of the cytoskeleton.
  • A condensation of the chromatin.
  • Degradation of the DNA into fragments.

The changes associated with cell death arising from injury is referred as necrosis.

Comparison of morphologic changes that occur in apoptosis and necrosis

Apoptosis results in the programmed cell death of hematopoietic cells that does not induce a local inflammatory response.

In contrast,

Necrosis leads to the death of injured cells, results in the release of the contents of the cell, which may induce a local inflammatory response.

SCID mice ( severe combined immunodeficiency mice) is a major tool in studies to identify and characterize the human hematopoietic stem cell. SCID mice are used as an in vivo assay system for the presence and function of HSCs.

SCID  mice are unable to mount adaptive immune responses such as those that act in the normal rejection of foreign cell, tissues, and organs as they do not have B and T lymphocytes

Consequently,

SCID  mice do not reject transplanted human cell populations containing HSCs or tissues such as thymus and bone marrow.

This system has made possible the study of subpopulations of CD34+ cells and the effect of human growth factors on the differentiations of various hematopoietic lineages.

Red blood corpuscles or Erythrocytes

In all the vertebrates except mammals, the erythrocytes are oval, biconvex and nucleated. In mammals except for camel and IIama, the mature erythrocytes are circular, biconcave and non-nucleated. The biconcave shape increases the surface area to volume ratio and the absence of nucleus increases the hemoglobin contents and also increases the motility of the cells.

The number of erythrocytes differs in different animals as well as with the physiological state of an individual.The RBCs are much more than the WBCs.The total number of RBCs per μL is called RBC count. Hemocytometer is used to determine RBC count.

When RBC count decreases then it is called anemia while RBC count increases much more than the normal level in polycythemia. The decrease in the number of RBCS is called erythroctopenia which lead to the Hypoxia (O2 deficiency in the body tissues).

A human RBC is bounded by an elastic and semipermeable plasma membrane (also called Donnan’s membrane) which enable it to squeeze through narrow capillaries. The mature mammalian characterized by the absence of a nucleus, mitochondria, and endoplasmic reticulum so there is low consumption of oxygen by itself and is primarily concerned with the transport of oxygen from the respiratory organs to the body tissues.

Hemoglobin is a purple-colored, iron-containing respiratory pigment present in the cytoplasm of red blood cells. Hemoglobin formed of 4 heme groups and a protein called globin. Each heme group contains an iron-containing porphyrin ring formed of 4 pyrrole rings. Globin is formed of 4 polypeptide chains -2α and 2β chains. One RBC has about 280 million hemoglobin. The amount of hemoglobin per 100ml of blood is called hemoglobin count and is measured by an instrument called haemometer.

Due to the absence of the nucleus, the RBCs are short lived. The old and worn-out erythrocytes are destroyed by the reticuloendothelial cells of liver, spleen and bone marrow. The process is called hemolysis. The hemoglobin of haemolysed erythrocytes is changed into another iron-containing pigment called hemosiderin and the bile pigments bilirubin and biliverdin. The bone marrow can use most of the iron again in the formation of new hemoglobin while the bile pigments are expelled out of the body along with the fecal matter. Each RBC takes about 50000 circuits in the body before hemolysis. RBCs are haemolysed at the rate of about 2.5 million per second but are also formed at the same rate so the blood maintains their number.

Leucocytes or White blood corpuscles (W.B.C)

WBCs are much less in number than RBCs (1:600). The total number of leucocytes per microlitre of per cubic millimeter is called total leucocyte count (TLC) and is a diagnostic feature of many diseases. The number of WBCs in a healthy person ranges from 5000 to 10000 per cubic millimeter of whole blood. Average WBC count is 7000 per cubic millimeter. But in an acute infection like appendicitis or pneumonia, the total leucocytes increase up to 20000 to 30000 per cubic millimeter of blood. This rise in WBC count is called leucocytosis while the fall of WBC count below 4000 is called leucopenia, e.g., in folic acid deficiency and tuberculosis. Leukemia is the pathological increase in number and denotes one type of neoplastic disease (blood cancer). The formation of leucocytes occurs in bone marrow, Peyer’s patches, lymph nodes, thymus, spleen, etc. and is called leucopoiesis.

On the basis of cytoplasmic granules, the leucocytes are divided into following two categories:

  1. Granulocytes
  2. Agranulocytes

GRANULOCYTES

Granulocytes have granular cytoplasm and lobed nucleus, so also called polymorphonuclear leucocytes. These are produced in the red bone marrow from the precursor cells called myeloblasts (myeloid tissue). These form about 65% of total leucocytes. These are three subtypes by the shapes of their nuclei and the staining reactions of their granules.

Neutrophils comprise about 62% of the total number of white cells so most abundant sub-type. These vary in size from 10-20µm. The cytoplasm is with fine granules which stain with both acidic and basic dyes so appear violet in color.These granules are lysosomes and Golgi bodies. The nucleus is 3-5 lobed. The lifespan is 10-12 hours. These are the main phagocytic cells of the body and engulf the microbes by phagocytosis, so neutrophils are called soldiers of the body. These are attracted to an infected area by chemotaxis. If the infection is massive or microbes are very virulent, many neutrophils die, known as pus. The accumulation of pus at one place is called an abscess. Neutrophils also help in sex-differentiation as the neutrophils of female show ‘drum stick’ or ‘barr-body’ attached to one of the nuclear lobes. It represents an inactivated X-chromosome, so also called sex chromatin.

Basophils comprise about 0.5-2% of the TLC so are least in number. These vary in size from 8-10µM. The cytoplasmic granules are coarse which take up basic stains like methylene blue, so appear blue in color. The nucleus is 2 or 3 lobed or S-shaped. Their lifespan is 8-12 hours. They secrete heparin and histamine and thus have a significant role in regional anticoagulation.

Acidophils constitute about 2-4% of the TLC. These are slightly larger in size than the neutrophils and size range is 10-15µm. The cytoplasmic granules are coarse and take acidic stains like eosin, so also called eosinophils. The nucleus is bilobed. Therlifespanan is 14 hours. These increase in number in allergic such as asthma or hay fever, and in parasitic infections. e.g., Ascariasis. Acidophils also help in the healing of wounds as destroy toxins of the microbes.

AGRANULOCYTES

These are non-granular white blood cells that contain non-lobulated nuclei. These form about 35% of the total leucocytes. These are divided into two sub-types:

Monocytes are the largest sized leucocytes ranging from 12-15µm in diameter but may be up to 20µm. These form about 5.3% of all the leucocytes. The number of monocytes varies from100-400 per cubic mm of blood. The nucleus is oval shaped, kidney or horseshoe shaped and is usually excentric. These are usually formed in the lymph nodes and the spleen and the spleen from the precursor cells called monoblast. These are highly motile and phagocytic in action and engulf the bacteria, so these form the second line of defense. These also differentiate damaged and dead cells to clean the body.

Lymphocytes constitute about 30% of TLC. Their number varies from1500-2700 per cubic mm of blood. Their size ranges from 8 to 12µM. The nucleus is large and rounded so that cytoplasm forms a thin peripheral layer. Depending upon size, there are two types of lymphocytes-small(about 7m) and large lymphocytes (20m). Lymphocytes are formed in the thymus and lymphoid tissues like lymph nodes, spleen, tonsils, etc. from the precursor cells called lymphoblasts. The primary function of the lymphocytes is to produce antibodies and opsonins.

 

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