Myeloid Stem Cells

Definition, Development and Differentiation



Definition


 

Commonly known as myeloid progenitor cells, myeloid stem cells are derived from hematopoietic stem cells. They undergo differentiation to produce precursors of erythrocytes, platelets, dendritic cells, mast cells, monocytes, and granulocytes.

Compared to their precursor, myeloid stem cells have restricted development potential and are therefore only capable of giving rise to several cell types. For this reason, they are classified as oligopotent progenitors. 

 



Some of the signaling molecules involved in the differentiation of myeloid stem cells include:

 

  • Interleukin 3
  • Interleukin 5
  • Granulocyte colony-stimulating factor (G-CSF)
  • Agranulocytic-colony stimulating factors (AG-CSF)

 

* Myeloid stem cells are also referred to as CFU-GEMM (Colony-forming unit − granulocyte, erythroid, macrophage, megakaryocyte) and are characterized by CD34, HLA-DR markers, and CD-64


* While most of the cells in the myeloid stem cell lineage are produced through the bone marrow intermediates, studies have shown some of these cells to directly develop from progenitors of the yolk sac.

Here, one of the best examples are tissue-resident macrophages

 



Development of Myeloid Stem Cells



Myeloid stem cells originate from multipotent stem cells known as hematopoietic stem cells in the red bone marrow. These cells are responsible for the continual replenishment of all blood cell types in the body. 

Theoretically, hematopoietic stem cells were suggested to renew themselves through symmetrical and asymmetrical cell division. Over time, various research studies have shown this to be the case.

While symmetrical cell division of these cells results in the production of two identical stem cells, asymmetrical division gives rise to a single stem cell (identical to the parent cell) and another differentiated cell. 

Here, asymmetrical division results in the production of myeloid stem cells or lymphoid stem cells.

 

* Based on a number of studies, hematopoietic have been shown to be capable of producing myeloid stem cells without dividing first. 

 

The development of myeloid stem cells from hematopoietic stem cells is known as myelopoiesis. This involves a number of important steps that are regulated by transcription factors like PU.1. 

Here, these transcription factors influence the expression of myeloid-specific genes and consequently the commitment of these cells to the myeloid lineage. Moreover, they regulate the differentiation of myeloid stem cells to progenitors that ultimately give rise to more specialized cells. 

 

* The commitment of hematopoietic stem cells to the lymphoid or myeloid lineage is known as lineage bias.

 

As mentioned, one of the transcription factors involved in the development of myeloid stem cells is the PU.1. Also known as Spi-1, PU.1 belongs to the Ets (Erythroblast Transformation Specific) family and targets a number of genes including GM-CSF receptor alpha, integrin CD11B, and the G-CSF receptor among others. 

In the absence of this transcription factor, research studies involving mice have shown there to be an absence of monocytes and granulocytes. This is evidence that the absence of this transcription factor affects the differentiation of hematopoietic stem cells along the myeloid stem cell lineage. 


Apart from PU.1, some of the other factors involved in the development of myeloid stem cells include:


  • Core-binding factor family,
  • EBD family, 
  • Retinoic acid



Differentiation



Essentially, differentiation refers to the process through which a cell (unspecialized or partially specialized) matures into a more specialized cell. Here, one of the best examples already used is the maturation/development of hematopoietic stem cells into myeloid stem cells. 

While some studies have shown progenitor cells in some animals to be capable of self-renewal, this is very limited and only occurs within several days after they are produced. However, they rapidly proliferate and differentiate to give rise to progenitors that ultimately give rise to specialized blood cells. 

 

* The balance between proliferation and differentiation of hematopoietic stem cells into progenitor lineages is governed by various transcription factors. 

 


Monocytes/Macrophages



Monocytes are some of the cells produced through the myeloid stem cells lineage. Here, studies have shown the cytokine, macrophage colony-stimulating factor (M-CSF) to influence the proliferation of myeloid stem cells followed by their differentiation to produce monoblasts that continue differentiating to produce functional monocytes. 

This cytokine, on the other hand, is under the regulation of transcription factors Ets- and AP-1.

 

* Cytokines like M-CSF are usually released in response to given stressors or infections.


* Some of the other signaling molecules associated with this process have been shown to include interleukin 3 and interleukin 5.

 

Under stress conditions or in the case of an infection, monocytes and macrophages (monocytes that leave the blood to reside in various tissues) produce M-CSF which activates the differentiation process that results in the production of more monocytes from the myeloid stem cells.

According to studies, the production of M-CSF by these cells (monocytes and macrophages) is influenced by a number of factors including GM-CSF, Interleukin 3, and TNF-Alpha among others. 

 


Granulocytes



Granulocytes include white blood cells that are characterized by small granules (proteins) in their cytoplasm. These include neutrophils, eosinophils, and basophils.

These cells originate from derivatives of the myeloblast which in turn originates from the myeloid stem cells. 

Here, differentiation of myeloid stem cells to produce the myeloblast is under the influence of several factors that include:

 

  • G-CSF (Granulocyte colony-stimulating factor)
  • Interleukin 3
  • Interleukin 5

 


In healthy individuals, the serum contains low levels of G-CSF. In the event of an infection, expression of this factor in serum increased which in turn increased the number of granulocytes.

Like mature neutrophils, myeloid stem cells have receptors for granulocyte colony-stimulating factor (G-CSFR). 

With the increase in the level of this factor (G-CSF), myeloid stem cells have been shown to undergo proliferation before differentiating to produce myeloblasts. This process is repeated in the new progenitors ultimately resulting in the production of mature granulocytes. 

Like M-CSF, increased expression of G-CSF is influenced by a number of factors. These include interleukin 1β, lipopolysaccharide, as well as the tumor necrosis factor-alpha. In the presence of LPS, for instance, macrophages have been shown to release G-CSF thus increasing the level of this factor in the serum. 

Once this increase is detected by the myeloid stem cells, increased proliferation and differentiation occurs thus resulting in increased production of neutrophils and other granulocytes. 

 

* Like G-CSF, GM-CSF, (Granulocyte-macrophage colony-stimulating factor), also promotes the differentiation process that results in the increased number of granulocytes.

 


Megakaryoblast



The megakaryoblast is a large progenitor cell that undergoes differentiation to give rise to thrombocytes (platelets). As is the case with the monoblast, which gives rise to monocytes, and myeloblast, which gives rise to granulocytes, the megakaryoblast is the descendant of myeloid stem cells. 

Here, the differentiation of myeloid stem cells to produce megakaryoblast is influenced by the cytokine thrombopoietin produced in the liver and kidneys. 

 

The process through which progenitors in the bone marrow ultimately give rise to mature megakaryocytes is known as megakaryopoiesis. As mentioned, thrombopoietin (TPO) is one of the most important cytokines involved in this process. 

Following the binding of the cytokine to their receptors (Mpl) in the hematopoietic precursors, studies have shown them to influence differentiation along the megakaryocytic lineage. Apart from the myeloid progenitors, the receptor has also been identified in the megakaryocyte-erythroid progenitor (MEP). 

As mentioned, the cytokine thrombopoietin is produced in the liver and kidney before being released in plasma. With an increased level of the cytokine in circulation, it can influence the actions of the cells with Mpl receptors (hematopoietic stem cells, myeloid stem cells, and megakaryocyte-erythroid progenitors).

 


Differentiation of Myeloid Stem Cell sin Erythropoiesis



Erythropoiesis refers to the process through which red blood cells are produced. While erythropoiesis is a natural process that allows for the replacement of dead or damaged cells (resulting from natural cell death or infections like malaria etc.), it may also be influenced by such conditions as hypoxia and anemia, etc. 

In the event of these conditions, a cytokine known as erythropoietin is produced in the kidney to influence the production of red cells in the bone marrow.


This process involves several important steps that include:

 

·       Activation of the hematopoietic stem cells - As is the case with the other cells, the production of red cells start with the activation of hematopoietic stem cells located in the bone marrow. Here, studies have shown this activation to result from soluble macromolecules as well as cell to cell interaction. Following this initial activation, these cells undergo differentiation to produce the myeloid stem cells 


·       Differentiation of myeloid stem cells - The second general step involves differentiation of myeloid stem cells to produce more differentiated progenitors. Here, the cytokine erythropoietin plays a key role in the differentiation of myeloid stem cells to produce megakaryocytic erythroid progenitors and/or granulocyte-myeloid progenitors. 


·       Differentiation of megakaryocytic/erythroid progenitors - The next step in the production of red blood cells involves the proliferation and differentiation of megakaryocytic erythroid progenitors to produce colony-forming units that are also capable of responding to the cytokine erythropoietin.

These cells then undergo differentiation to produce progenitors known as erythroblasts (normoblasts) within the bone marrow. 


* As they mature, normoblasts lose a number of organelles as well as their nucleus as they transform into reticulocytes. Similarly, reticulocytes lose more organelles as they mature into functional red cells. 



Myeloid Stem Cells Vs Lymphoid Stem Cells



Like myeloid stem cells, lymphoid stem cells also originate from the hematopoietic stem cell. The two types of cells, myeloid stem cells and lymphoid stem cells, have a number of similarities and differences which include:

 


Similarities


They originate from hematopoietic stem cells - As mentioned, both myeloid stem cells and lymphoid stem cells originate from hematopoietic stem cells (multipotent cells located in the red bone marrow).

Here, the differentiation of hematopoietic stem cells results in two lineages, lymphoid and myeloid, which differentiate further to produce different types of cells. 

 

They are oligopotent progenitors - While the term "stem cells" is used here, it's worth noting that myeloid stem cells and lymphoid stem cells are actually progenitors.

While they are capable of differentiating to produce several types of cells, the two types of cells are incapable of self-renewal (or are characterized by very limited self-renewal) and therefore do not qualify as stem cells.

As oligopotent cells, they can only give rise to several cell types compared to their precursors. However, they have higher potency compared to their descendants. 

 

They can be found in the bone marrow - In adults, both myeloid stem cells and lymphoid stem cells are found in the bone marrow.

Along with the other stem cells and progenitors, the two types of cells differentiate within the bone marrow to produce low potent progenitors that ultimately give rise to mature functional cells.

Unlike stem cells and progenitors, mature, functional cells enter blood circulation to migrate to other tissues. 

 


Differences between Myeloid Stem Cells and Lymphoid Stem Cells


Interleukin-7 receptor - One of the main differences between myeloid stem cells and the lymphoid stem is with regards to IL-7. IL-7 is a receptor that is expressed on lymphoid stem cells and therefore plays an important role in the differentiation along the B and T cells lineage.

The receptor is absent in myeloid stem cells and therefore has no role to play in this cell type. The presence or absence of this receptor has allowed researchers to differentiate between the two types of cells in some organisms. 

 

Lineage - While lymphoid and myeloid stem cells originate from hematopoietic stem cells, differentiation proceeds along separate lineages resulting in the production of different types of cells.

In the presence of signaling molecules, myeloid stem cells differentiate to produce progenitors that ultimately give rise to platelets, granulocytes (basophils, neutrophils, and eosinophils), monocytes, as well as dendritic cells.

Lymphoid stem cells, on the other hand, differentiate to produce progenitors that produce lymphocytes, natural killer cells, and dendritic cells.

According to studies, cells of the lymphoid lineage make up about 15 percent of the total cells in the bone marrow.  

 

Colony-stimulating factors - In both the myeloid and lymphoid lineages, blood growth factors known as colony-stimulating factors are involved in the differentiation of progenitors resulting in the production of functional white blood cells.

While the granulocyte colony-stimulating factor influence the differentiation of myeloid stem cells to produce granulocytes, especially neutrophils, the agranulocytic colony-stimulating factor is involved in the myeloid stem cell lineage and activates the production of lymphocytes (B and T cells).

 

 

Return to:


Erythrocytes

Platelets

Dendritic cells

Mast cells

Monocytes

Granulocytes

Lymphocytes

Natural Killer Cells


More about Cells:


Cell Proliferation

Cell Adhesion

Cell Signaling

Pentose Phosphate Pathway


Return to learning about Stem Cells

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References

 

Asterios S. Tsiftsoglou, Ioannis S. Vizirianakis and John Strouboulis. (2008). Erythropoiesis: Model Systems, Molecular Regulators, and Developmental Programs.

 

Athanasia D. Panopoulos and Stephanie S. Watowich. (2008). Granulocyte Colony-Stimulating Factor: Molecular Mechanisms Of Action During Steady State And ‘Emergency’ Hematopoiesis.

 

Colin A Sieff. (2011). Regulation of myelopoiesis.

 

Leila J. Noetzli, Shauna L. French, and Kellie R. Machlus. (2019). New Insights Into the Differentiation of Megakaryocytes From Hematopoietic Progenitors.

 

Tatyana Grinenko et al. (2018). Hematopoietic stem cells can differentiate into restricted myeloid progenitors before cell division in mice.

 

 

Links 

 

https://ashpublications.org/blood/article/119/11/2431/29587/Do-HSCs-divide-asymmetrically