How Are Blood Cells Formed in Our Body

The first blood cell of our body is an erythroblast (a primitive red blood cell), which is made by the mesoderm of the yolk sac, in a structure called blood island.

The cellular components of blood are formed from a unique blood cell termed hematopoietic stem cell (HSC). A single HSC can proliferate to give rise to several daughter HSCs which mature to form different types of blood cells. This process of formation of blood cells through the proliferation and differentiation of HSC is termed hematopoiesis.

Only a few thousand HSCs present at birth ensure the constant supply of blood cells throughout the entire lifetime of an individual. This write-up provides a brief outline of how blood cells are formed in the body through the process of hematopoiesis, and what are the sites for hematopoiesis in the human body.

Stem cells have the ability of self-renewal and to give rise to other types of cells. The ones that can give rise to a single cell type are termed unipotent stem cells, whereas those that can give rise to several types of cells are termed multipotent stem cells. HSC is a multipotent stem cell and is dedicated to the formation of blood cells.

In adults, HSCs are present in the bone marrow and grow on a meshwork of cells called stromal cells. These cells support the growth and differentiation of HSC by secreting growth factors and chemical messengers, including cytokines. This cellular matrix and the secreted factors are collectively termed hematopoietic-inducing environment (HIM).

The HSC can follow two different pathways:

» The lymphoid pathway that gives rise to the lymphoid lineage of blood cells (T cells, B cells, and NK cells) as well as dendritic cells.
» The myeloid pathway that gives rise to the myeloid lineage of blood cells (granulocytes, monocytes, and mast cells) as well as dendritic and red blood cells.

As the level of differentiation increases along a particular pathway, the ability of proliferation decreases. The mature blood cells lack the capacity to self-renew and have a finite lifespan.

The lymphoid pathway begins with the differentiation of HSC into the common lymphoid progenitor. The resultant lymphocytes account for 20 - 40% of the white blood cells present in the bloodstream. The three main populations of lymphocytes generated through the lymphoid pathway are:

The common lymphoid progenitor differentiates into a B-cell progenitor or pro-B cell, which is considered to be the earliest distinguishable cell of the B-cell lineage. The antibody formation process begins in this cell, through the rearrangement of immunoglobulin genes to form a segment of the heavy chain of antibodies.

This pro-B cell develops into pre-B cell, through interaction with the stromal cells and cytokines, especially IL7, present in the stromal microenvironment. Here, further rearrangements occur at the immunoglobulin gene locus, and the heavy chain for IgM antibody is expressed onto the membrane along with a surrogate light chain.

Only those cells successful in such expression, proceed to maturation and form the immature B cell, which then matures in an antigen-dependent manner. The immature B cells that express antibodies capable of binding to proteins of the body itself are eliminated by inducing them to commit suicide.

The development of T cells begins with the differentiation of the common lymphoid progenitor to form a progenitor T cell or T-cell precursor. This precursor migrates through blood to reach the thymus, where further maturation occurs due to molecular signals and interaction with the thymic stromal cells.

The T-cell precursor develops into a cell called double negative pro-T cell, since it lacks the two characteristic surface molecules called CD4 (cluster of differentiation 4) and CD8 (cluster of differentiation 8) that are present on T-helper cells and cytotoxic T cells, respectively.

Here, gene rearrangements take place during the different stages of maturation to form the T-cell receptor, and the CD4 and CD8 molecules are expressed on the surface.

This cell is termed as the double positive pro-T cell, which differentiates into either CD4+ T-helper cell or CD8+ cytotoxic T cell. Of these, the ones that have a high affinity to self-antigens are eliminated through apoptosis, and the remaining ones are released into the circulation.

These cytotoxic lymphoid cells develop from immature NK cells formed in the bone marrow, through differentiation of the common lymphoid progenitor.

The immature NK cells enter the bloodstream and migrate to the thymus, lymph nodes, tonsils, and spleen for further maturation into resting NK cells. The resting NK cells get activated in response to antigen stimulation, in order to perform its cytotoxic functions.

Analogous to the lymphoid pathway, the myeloid pathway begins with the differentiation of HSC into the common myeloid progenitor. This progenitor gives rise to the following populations of blood cells.

The first cell of the granulocyte series is the myeloblast, which forms through the differentiation of the common myeloid progenitor. Myeloblast develops into a promyelocyte, that contains non-specific granules in the cytoplasm.

With further division and differentiation, the number and specificity of the granules increases giving rise to:

• Eosinophil progenitor (eosinophilic myelocyte) which has granules that stain red on treatment with the acidic dye eosin. This cell further develops into an eosinophil.

• Basophil progenitor (basophilic myelocyte) granules stain blue when exposed to a basic dye. They mature to form the basophil population of blood cells.
• Granulocyte-monocyte progenitor either differentiates to form neutrophil promyelocyte that further develops into neutrophils, or monocytes that develop into mononuclear phagocytic cells like macrophages.

In response to molecular signal received in the form of the hormone erythropoietin, the common myeloid progenitor gives rise to an erythroid progenitor cell, that is committed to the production of red blood cells. The erythroid progenitor develops into an erythroblast, and hemoglobin formation begins.

Further division and differentiation results in the extrusion of nucleus and increase in hemoglobin formation to produce immature red blood cells called reticulocytes. These cells eliminate the nucleus as an adaptation for efficient oxygen transport. Reticulocytes are released from the bone marrow, and mature into red blood cells.

The myeloid pathway is also the route for formation platelets, in response to the hormone thrombopoietin. Proliferation and differentiation of the common myeloid progenitor gives rise to a cell called megakaryoblast. This megakaryoblast undergoes divisions to become a multinucleated large cell called promegakaryocyte, which has an extensive cytoskeleton.

It further undergoes cytoplasmic maturation to become the megakaryocyte, which gives rise to fragments containing parts of the cytoplasmic material. These fragments develop into platelets, and the remaining part of megakaryocyte that comprises a polyploid nucleus and some cytoplasm around it, undergoes cell death by apoptosis.

Dendritic cells arise from many differentiation events at varied locations, through lymphoid and myeloid pathways. 4 major types of dendritic cells are Langerhans cells, interstitial dendritic cells, myeloid dendritic cells and lymphoid dendritic cells. The former 3 arise from the common myeloid progenitor, and the last from the common lymphoid progenitor.

During embryonic stage of development, blood formation takes place in the yolk sac. The first cell is a large nucleated erythroblast or primitive red blood cell. It is called primitive, as it is similar to non-mammalian red blood cells. Blood formation occurs in a structure called blood island, which gives rise to many other parts of the circulatory system.

During fetal development, fetal HSCs migrate to the liver, spleen, and bone marrow; blood formation initiates in these organs. By the ninth month of gestation, bone marrow becomes the major site for hematopoiesis, and little or no blood formation occurs in the liver and spleen.

The complex process of hematopoiesis provides the most important component of blood, i.e., blood cells, which are essential for the viability of every other cell of our body. Each and every cell of our body depends on the few thousand HSCs to produce blood cells which provide them with nourishment as well as protection.