Haematopoiesis

The differentiation of the hematopoiesis and the role of hematopoietic differentiation in immunity.

On average, about 10^11–10^12 new blood cells are produced daily to keep steady-state levels in the blood circulation. But, what causes the formation of these complex cells? Does the process have any adverse effects? Can we manipulate it at our convenience? All you want to know about Hematopoiesis is in our new blog. So get ready and feed your brain cells with our new blog on “Hematopoiesis”.

Types of hematopoietic differentiation pathways for different cells

Multipotent hematopoietic stem cells (HSC) are the stem cell of hematopoietic. Hematopoietic differentiation is expressed by all the cells. But the pattern of hematopoiesis varies. The production of the three types of blood cells namely RBC (Red Blood Cells), WBC (White Blood Cells), and the platelets are referred to as trilineage hematopoiesis. Initially, the transformation of the HSC into each of these cells occurs. This process is known as the myeloid progenitors (CMP).

At each of the further stages in the process, the precursor cells get more organized. For instants, CPM has to under 5 stage changes before forming becoming the erythrocytes. Whereas, they have to transform three times before forming platelets.

Figure.1 — Hierarchy of hematopoietic cells during normal differentiation of bone marrow-derived.

The process varies for the White Blood Cells as there are many types of white blood cells. Each type of WBC has a distinct pathway. Initially, they transform into myeloblasts. Myeloblasts are the immature form of the WBC. The formation of the myeloblasts occurs in the bone marrow. They later transformed into granulocytes. Granulocytes are composed of neutrophils, basophils, and eosinophils. For the WBC to transform into neutrophils, basophils, and eosinophils, they have to undergo four-stage development.

The WBC has to become a macrophage. The macrophage has phagocytotic properties. Their primary function is the detection, phagocytosis, and destruction of foreign bodies (primarily bacteria). They help to remove the dead cells and initiate inflammation by releasing molecules.

Another pathway of hematopoietic differentiation produces the T cells and the B cells. To produce lymphocytes, the cells transfer into common lymphoid progenitors. These common lymphoid progenitors later transform into lymphoblasts. The lymphoblasts then transfer into T cells and the B cells. When the B cells are exposed to infections, they transform into plasma.

Hematopoietic Differentiation of Human Embryonic Stem Cells

The human embryonic stem cell (hESCs) provides hematopoietic stem cells which can be a potential alternative for bone marrow transplantation. The hESC-derived differentiating cells formed hematopoietic progenitors; this corresponds to the highest CD34 expression. The primary and secondary hematopoietic engraftment can be carried out by the hESC-derived hematopoietic cells. TGF-b1 and TGF-b3 were identified as positive enhancers of hESC hematopoietic differentiation under transcriptional and functional analysis.

Figure. 2 — Human embryonic stem cells.

The stromal cells derived from hematopoietic niches can enhance the Hematopoietic Differentiation of hESCs. The hematopoietic Gen gets activated during hESC Coculture.

Disease and hematopoietic cells

The differentiation of hematopoietic cells due to oncogenes causes many types of leukemia (such as acute myelogenous leukemia, AML). The subpopulation of leukemia cells that are of low frequency is called the Leukemic stem cells (LSCs). Their stem cell properties are distinct from the bulk leukemia cells. The leukemic stem cell has oncogenes that function with them. Therapeutic targeting of these oncogenes is necessary.

Measuring the effect of oncogenes on primary human hematopoietic stem cells (HSCs) requires prolonged incubation time. However, the properties of leukemic stem cells can be modified by inhibiting the oncogene’s effect on the multipotent hematopoietic progenitor cell. This can also complement the clinical use of cytotoxic drugs.

Research has shown similarities between the cancer tissues (sarcoma) and the embryonic tissue. The sarcoma is generally soft tissue that is formed on the muscles, blood vessels, tendons, ligaments, fibrous tissues, etc… These tissues generally lie dormant but are activated at times and become cancer. Research shows that cancer arises from the tissue stem cells in adults. Cellular events at hepatocarcinogenesis show that cancer can arise from cells at various stages of differentiation. Once activated the normal cell transforms first into hyperplasia. Then they become dysplasia and finally they transform into cancer cells.

Figure.3 — Stages involved in the formation of cancer cells.

The primitive form of the hematopoietic cell is the multi/pluripotent these are found in the bone marrow. In the bone marrow, they are present as resting stem cells. They don’t proliferate under normal conditions. To stimulate the proliferation stress has to be induced. Like loss of blood or lack of oxygen.[1]

The primitive hematopoietic cell is the parental cell for a wide range of proliferating cells found in the bone marrow (transit-amplifying progenitor cells). The progenitor cells give rise to progeny. These progenies differentiate and form mature circulating blood cells.

The hematopoietic cells also contribute to multiple autoimmune diseases. The mature human CD24 protein contains 32 residues and is linked to the cell membrane via a GPI anchor. It is a heat-stable antigen. Autoimmune diseases are cases in which the immune system mistakes part of your body as foreign and attacks these parts. This leads to various diseases such as Rheumatoid arthritis and Systemic lupus erythematosus.

CD24 and the pathogenesis of autoimmune diseases have a strong genetic association. The single-nucleotide polymorphisms a genetic variant of CD24 is etiologically relevant to autoimmune diseases (such as systemic lupus erythematosus and multiple sclerosis). CD24 acts as the regulator in the T and B cell homeostasis.

Figure. 4 — Hematopoietic Reprogramming.

Understanding the mechanism of the CD24 pathway and its impact on the regulatory axis of the immune system will aid in improving our knowledge of the pathogenesis of autoimmune diseases.[2] This, in turn, will spur the development of CD24 as a biomarker in terms of diagnosis, therapy, and prognosis for the CD24-related pharmacological agents to treat autoimmune diseases.

Conclusion:

Uncontrolled hematopoietic differentiation can cause diseases like cancer. We can use the antigen properties of the hematopoietic cell to produce new therapeutic methods. Hence, hematopoiesis can be used for therapeutics.

References:

• Wechsler, Henry, et al. 1983. “The New England Journal of Medicine Downloaded from Nejm.Org at UNIVERSITY OF OTAGO on May 20, 2014. For Personal Use Only. No Other Uses without Permission. From the NEJM Archive. Copyright © 2010 Massachusetts Medical Society. All Rights Reserved.” N Engl J Med 308(2): 97–100.
• Tan, Yixin, et al. 2016. “CD24: From a Hematopoietic Differentiation Antigen to a Genetic Risk Factor for Multiple Autoimmune Diseases.” Clinical Reviews in Allergy and Immunology 50(1): 70–83.
• Robb, L. 2007. “Cytokine Receptors and Hematopoietic Differentiation.” Oncogene 26(47): 6715–23.
• Yeh, Jing Ruey J., et al. 2009. “Discovering Chemical Modifiers of Oncogene-Regulated Hematopoietic Differentiation.” Nature Chemical Biology 5(4): 236–43.
• Ledran, Maria H. et al. 2008. “Efficient Hematopoietic Differentiation of Human Embryonic Stem Cells on Stromal Cells Derived from Hematopoietic Niches.” Cell Stem Cell 3(1): 85–98.
• Asakura, Atsushi, and Michael A. Rudnicki. 2002. “Side Population Cells from Diverse Adult Tissues Are Capable of in Vitro Hematopoietic Differentiation.” Experimental Hematology 30(11): 1339–45
• Dykstra, Brad, et al. 2007. “Long-Term Propagation of Distinct Hematopoietic Differentiation Programs In Vivo.” Cell Stem Cell 1(2): 218–29.
• Kosti, Edit et al. 2016. “Cross-Tissue Analysis of Gene and Protein Expression in Normal and Cancer Tissues.” Scientific Reports 6(January): 1–16. http://dx.doi.org/10.1038/srep24799.
• Tamayo, Pablo, et al. 1999. “Interpreting Patterns of Gene Expression with Self-Organizing Maps: Methods and Application to Hematopoietic Differentiation.” Proceedings of the National Academy of Sciences of the United States of America 96(6): 2907–12.