Hematopoiesis And Blood Cells

Get ready to improve your Physiology preparation with this detailed blog post on Hematopoiesis And Blood Cells. You will find everything you need to ace this topic in this blog post. 

Hematopoiesis is the formation of blood’s cellular components or to put it more simply, blood cell production. The human body is continuously creating new blood cells to replace the old ones and this process ensures that the body has a healthy supply of blood cells to supply oxygen to all the tissues, fight infection and clot blood to heal injuries. This is one of the most important topics for NEET PG preparation. 

• Hematopoiesis is a complex process of the generation of mature blood cells. It is a multi-layered process by which hematopoietic stem cells generate mature blood cells.

Hematopoiesis

• Hematopoiesis starts in humans on and around day 19 of the gestation period.
• The hematopoiesis occurs in the yolk sac, and after 3rd week of gestation, hematopoiesis also occurs at mesodermal structures like the aorta, gonads, and mesonephros.
• Then this hematopoietic activity shifts from the yolk sac and mesodermal region to the liver, spleen, and lymph node. Further, it shifts to the bone marrow around 20 weeks of gestation. This is the major switchover.
• The hematopoietic activity of long bones will decrease during puberty, and the activity will only continue in membranous bones like vertebrae, sternum, ribs, and ilia.
• This hematopoiesis activity is shown in the image. 

• The x-axis shows the fetal months and the age of a human in years.
• Before birth, hematopoiesis occurs at the level of the yolk sac and decreases at 2 months of gestation. 
• The bone marrow does the main hematopoiesis at the time of birth. 

Site of Hematopoiesis: Niche

• The stem cells of hematopoietic origin are located in the venous sinus region of bone marrow.

• The stem cells mainly reside in the perivascular space, particularly in the region of the trabecular bone.
• Certain stem cells remain close to the endosteal region of the bone. 
• These are the areas where hematopoietic cells reside; this area is known as the niche of hematopoietic stem cells. 
• Other cells also reside in a community in the bone marrow. These cells are macrophages, fat, osteoblast, and osteoclast cells. These cells are responsible for signaling, proliferation, and differentiation. This community is known as the hematopoietic niche or hematopoietic inductive microenvironment.
• The hematopoietic niche is located in two areas. These areas are
  • Perivascular Space
  • Endosteal Niche: It is mainly important during stem cell transplantation (bone marrow transplantation). In chemotherapy, this niche gets damaged and results in the rejection of stem cells into the donor.

Cells in the Hematopoietic Niche

• Mesenchymal and endothelial cells are in the niche, which secretes a factor known as a kit ligand or CXCL 12. These factors are responsible for the development of hematopoietic stem cells.
• Macrophages, megakaryocytes, osteoblast, and osteoclast cells secrete transcriptional factors like Bmi-1 and microRNA processing enzymes like Dicer.

Stem Cells

• The stem cells should have two important properties.
  • SELF-RENEWAL- The stem cells should be able to generate different kinds of cells independently without any differentiation to maintain their population.
  • Differentiation- This is the property of stem cells to give rise to mature cells.
• Stem cells divide in three major ways:
  • The first type will give rise to two cells identical to the mother cell. These cells will join hematopoietic stem cells, so this is self-renewal.
  • In the second type, daughter cells are different from the mother cells and will follow the differentiation path.
  • Hematopoietic stem cells will divide in a way by which one cell will have the same character as the mother cell, and it is considered to be self-renewal. Still, the other daughter cell will not have the same character as the mother cell and will follow a differentiation path.
  • These pathways are given in the image.

Types of Stem Cells

• Totipotent stem cells: this cell can produce the whole organism, including the placenta. When supporting media is given to one cell of the 8-celled stage of an embryo, it will give rise to the whole organism.
• Pluripotent Stem Cells: They can generate whole organisms but not the placenta.
• Multipotent Stem Cells:  These will form only one lineage of cells.
• Hematopoietic stem cells are pluripotent stem cells, and then they will be converted to multipotent stem cells and give rise to other blood cells. This multipotent stem cell is then converted to a progenitor, as shown in the figure.
• The differentiation increases when moving towards the mature part, whereas stem cells' self-renewal property is high.
• The hematopoietic stem cells are converted to multipotent stem cells, giving rise to two progenitor types.
• Common Myeloid Progenitor forms two cell lines: granulocyte monocyte progenitor and megakaryocyte E progenitor.
  • The granulocyte monocyte progenitor lineage has granulocyte colony-forming units (CFU) and monocyte colony-forming units (CFU).
  • G-CFU gives rise to neutrophils, eosinophils, and basophils; M-CFU gives rise to monocytes.
  • The cytokines responsible for developing the neutrophil series of granulocyte is GCSF. IL-15(interleukin 15) is responsible for eosinophil development, and for the better development of basophil lineage, IL-3 (interleukin 3) is required.
  • Megakaryocyte E progenitors give rise to erythrocyte CFU to form RBC and megakaryocyte CFU to form platelets.
• Common Lymphoid Progenitor is divided into two lineage B cell progenitor lineage and T/NK cell progenitor lineage. Both these lineages are formed using IL-7 cytokine.
  • B cell progenitor gives rise to mature B cells under the influence of IL-4 cytokine.
  • T//NK cell progenitors give rise to T cells under the influence of IL-2 and form NK- cells under the influence of IL-15. 

Blood Cells

RBC

It is biconcave in shape with a diameter of 7.2 micrometers.

• The surface area of RBC is 120-180 µm².
• The volume of a single RBC is 90 fL.
• The advantages of biconcave shape lie in the flexibility of RBC, greater surface area: volume ratio, and easy exchange of O₂ and CO₂. 

Erythropoiesis of RBC

• The erythropoiesis of RBC takes place in 6 different stages, and each stage has a difference between size, nucleus, cytoplasm, Hb, and mitosis. These stages are shown in the following image. 
• During the development process, the common myeloid progenitor, the first cell formed in RBC, is proerythroblast. It is a big cell of blue color cytoplasm and large nucleus.
• Going further to erythrocytes, the cell becomes pinkish and decreases in the size of the cell, and the nucleus size increases, but there is an increase in Hb content (forms pinkish color). 
• Early normoblast is also known as basophilic normoblast. Intermediate normoblast is also known as polychromatophilic normoblast.
• Pronormoblast has deeply basic cytoplasm, and Hb will appear in adequate amounts in intermediate normoblast. 
• Hb at the intermediate normoblast stage is so high that Giemsa stain can stain these cells. Because of adequate Hb, some pinkish color will appear around the nucleus.
• When this pink color appears, this condition is known as polychromasia.
• In late normoblast cells, the pink color is so much that the cell looks reddish pink, so this condition is called osteo chromatic.
• Hb will rise, but the cell will lose its nucleus, and this stage is called reticulocyte.
• Suppose the reticulocyte is stained with supra vital stain (methylene blue and brilliant crystals blue). A net-like structure due to ribosome and RNA.
• Mature RBC is formed after these reticulocytes with a high amount of Hb.
• With the increase in the development of RBC, the cell will lose its nucleus, the cell will decrease in size, and there will be an increase in Hb.
• Erythropoiesis requires many factors, and one of the important factors is erythropoietin (EPO) produced from peritubular epithelium cells of the kidney and perivenous hepatocytes from the liver. 
• The major stimulus of erythropoietin secretion is hypoxic conditions. RBC number will increase when erythropoietin secretion is increased by acting at the level of burst-forming units (more immature types of colonies).
• Erythropoietin stimulates several cells like CFU-E, BFU-E, proerythroblast, basophilic erythroblast, and polychromatophilic erythroblast shown in the image.
• Maximum erythropoietin receptor density is present on CFU-E, leading to the main action of erythropoietin at the CFU site.

Hemoglobin

• It contains 4 heme and 1 polypeptide globin (2 alpha and 2 beta chains). The structure of hemoglobin is shown in the image.
• There are different types of hemoglobin from the embryonic to the adult stage.
• Alpha and zeta globin chains are in the same family of globin genes: the alpha-globin gene coded by chromosome number 16.
• Beta globin chain family contains epsilon, gamma, beta, and delta, which are the family members expressed on chromosome 11.
• Zeta can combine with epsilon and gamma chains and form embryonic Hb.
• Alpha can combine with epsilon, gamma, beta, and delta chains to form different types of Hb.
• The interaction of these families is shown in the image.

• The depiction of the interaction of these families during the erythropoiesis is visible in the image.

WBC

• It is developed from hematopoietic stem cells, and the first cell is the myeloblast cell.
• With more maturation, the size of myeloblast decreases with the exception that the promyelocyte has the size of 12 micrometers and is the largest sized cell during WBC development.
• The nucleus size with maturation decreases.
• The primary non-specific granule appears first in promyelocytes with myeloperoxidase (MPO). This cell becomes the marker cell of WBC development.
• The primary granule converts to a second specific granule in the myelocyte stage, which is MPO negative, but it contains lactoferrin to give a pinkish appearance to the granule.

DLC

• The DLC contains granulocytes and agranulocytes.
• Granulocytes are neutrophils, eosinophils, and basophils. Agranulocytes are monocytes, small and large lymphocytes.

• To count the number of lobes in neutrophils, we use earneth count.

Arneth Count

• It is counting the neutrophils with different nuclear lobes and expressing their count as a percentage.
• If the combined value of N1, N2, and N3 is more than 80%, it indicates more immature cells in the blood and if the body catches bacterial infection, these immature cells will come into the blood.

Platelets

• The average size is 1-5 micrometers, and the volume of platelets is 5.8 µm³.
• ⅓ platelets of the total platelets present in the blood will remain inside the spleen.
• Platelets do not contain any nucleus, but they contain alpha and dense granules.
  • Dense Granules- they contain ADT, ATP, calcium, and serotonin.
  • Alpha Granules- These granules contain vWF, Factor V, VIII, integrin, cytokines, and TGF-β.
• Major regulator of platelet production is thrombopoietin which is synthesized in the liver.
• This synthesis increases in the presence of inflammation and specific interleukin (IL-6).

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