A. Production

Production of the cellular elements - erythocytes, leukocytes, and platelets

1.1 Hematopoiesis

Hematopoiesis is the process by which new blood cells are formed in the body. Hematopoiesis primarily occurs in the bone marrow, which is a soft, spongy tissue found inside the cavities of bones. Hematopoiesis is crucial for maintaining a constant supply of blood cells, including erythrocytes (red blood cells, RBCs), leukocytes (white blood cells, WBCs), and thrombocytes (platelets, PLTs).

The following terms are used when discussing hematopoiesis of a single cell line:

• Erythropoiesis: process of red blood cell production
• Leukopoiesis: process of white blood cell production
• Thrombopoiesis: process of platelet production

1.1.1 Locations

Locations of hematopoiesis differ during gestation (the period of development in the womb) when compared to after birth.

During gestation, hematopoiesis occurs in different locations as the fetus matures. The following is a breakdown of the specific locations of hematopoiesis during gestation. It is important to note that there is a gradual transition in the activity of hematopoiesis between the the following stages/organs.

Month 1, Yolk Sac: In the early stages of embryonic development, hematopoiesis first occurs in the yolk sac. The yolk sac is an extraembryonic membrane that provides nourishment to the developing embryo. It serves as the primary site of hematopoiesis during the first few weeks of gestation.

• Primitive erythrocytes are the majority cell produced. They cells help to supply oxygen to the developing embryo until other organs take over the role of erythropoiesis. Leukopoiesis and thrombopoiesis is less active.

Months 1 - 3, Liver: As the fetus develops, hematopoiesis shifts to the liver, typically around the sixth week of gestation. The liver becomes the major site of hematopoiesis during mid-gestation. Hepatic hematopoiesis plays a crucial role in producing red blood cells, white blood cells, and platelets.

• Erythropoiesis continues and produces erythrocytes that are more advanced in their development compared to those formed in the yolk sac. Likewise with leukopoiesis and thrombopoeisis. Leukopoeisis produces various types of white blood cells, including granulocytes (neutrophils, eosinophils, and basophils), monocytes, and lymphocytes. Thrombopoiesis produces larger, more mature megakaryocytes, which are responsible for generating platelets.

Months 3 - 9, Spleen: Around the ninth week of gestation, the spleen becomes a secondary site of hematopoiesis. It contributes to the production of red blood cells and lymphocytes. The spleen’s involvement in hematopoiesis decreases as the bone marrow takes over this function later in gestation. As the fetus approaches full-term, the bone marrow becomes the primary site of hematopoiesis, taking over from the liver and spleen.

• Erythropoiesis, leukopoiesis, and thrombopoiesis fully transition to a cycle of producing mature RBCs, WBCs, and PLTs, respectively.

Overall, during gestation, erythropoiesis, leukopoiesis, and thrombopoiesis starts in the yolk sac, progresses to the liver, progresses to the spleen, and finally settles in the bone marrow. This transition reflects the development and maturation of the hematopoietic system in the fetus.

After birth, hematopoiesis activity fully transitions to the bone marrow, which is termed medullary hematopoiesis. In certain conditions or diseases hematopoiesis can occur outside the bone marrow, such as the liver and spleen, and is termed extramedullary hematopoiesis.

Medullary hematopoiesis is the primary production of erythrocytes, leukocytes, and thrombocytes in health individuals. It is a process that is tightly regulated by various growth factors, cytokines, and hormones, ensuring the balance and production of different blood cell types as needed by the body. Locations with the highest hematopoietic activity is in the bone cavities of the axial skeleton, pelvis, and the proximal ends of long bones.

Extramedullary hematopoiesis is generally considered an abnormal process that is triggered by pathological conditions, such as chronic anemia, myelofibrosis, or bone marrow disorders. It is often a compensatory mechanism that is triggered when the bone marrow’s capacity to produce blood cells is compromised or when there is an increased demand for blood cell production.

1.1.2 Marrow Composition

Red marrow and yellow marrow are two types of bone marrow found within the cavities of bones.

Red marrow consists of a highly cellular and vascularized tissue matrix. It contains a mix of hematopoietic cells, adipocytes (fat cells), blood vessels, and supportive stromal cells. Red marrow is the active site of hematopoiesis, where blood cells are produced. It harbors hematopoietic stem cells (HSCs) that have the capacity to differentiate into various blood cell lineages, including erythrocytes, leukocytes, and thrombocytes. Red marrow has a soft, spongy texture and appears reddish in color due to its rich blood supply and the presence of numerous hematopoietic cells. In adults, red marrow is predominantly found in the axial skeleton (skull, vertebral column, ribs, and sternum), pelvis, and the proximal ends of long bones (such as the femur and humerus). Red marrow plays a vital role in maintaining the constant production of blood cells throughout life. It provides a supportive microenvironment and essential growth factors for the proliferation, differentiation, and maturation of blood cell precursors.

Stromal Cells are a diverse group of non-hematopoietic cells that provide structural support and contribute to the microenvironment of various tissues and organs, including bone marrow. These cells play critical roles in regulating hematopoiesis, immune function, tissue repair, and overall tissue homeostasis. In the bone marrow, stromal cells include:

Stromal Cell Types:

• Osteoblasts: These cells are responsible for bone formation and help maintain the structural integrity of the bone marrow.
• Endothelial Cells: Endothelial cells form the inner lining of blood vessels and contribute to angiogenesis, the formation of new blood vessels.
• Fibroblasts: Fibroblasts produce extracellular matrix (ECM) components, including collagen and other structural proteins, providing support and organization to the bone marrow.
• Adipocytes: Adipocytes are fat cells found in yellow marrow and contribute to energy storage.
• Mesenchymal Stem/Stromal Cells (MSCs): MSCs are multipotent cells that can differentiate into various cell types, including osteoblasts, adipocytes, and fibroblasts. They also have immunomodulatory properties and can support hematopoiesis.

Stromal Cells’ Functions and Roles:

• Structural Support: Stromal cells help maintain the structural architecture and organization of tissues, including the bone marrow, creating a supportive framework for other cells.
• Niche Regulation: Stromal cells create specialized microenvironments, known as niches, that regulate the behavior and function of hematopoietic stem cells (HSCs) and other cells within the bone marrow. They secrete various factors and cytokines that influence HSC self-renewal, differentiation, and migration.
• Cell-Cell Interactions: Stromal cells engage in intricate interactions with hematopoietic cells, immune cells, and other neighboring cells through direct contact or paracrine signaling. These interactions influence the development, differentiation, and function of various cell types within the bone marrow.
• Immune Modulation: Stromal cells within the bone marrow contribute to immune regulation and response. They can modulate the activity of immune cells, regulate inflammation, and influence the balance between immune tolerance and immune response.
• Extracellular Matrix (ECM) Production: Stromal cells synthesize and maintain the ECM components, which provide physical support, regulate cell adhesion, and play a role in cell signaling and tissue organization.
• Hematopoietic Support: Stromal cells, particularly MSCs, provide crucial support for hematopoiesis. They secrete factors such as cytokines (e.g., stem cell factor, interleukin-7) and provide physical contact and adhesion molecules that regulate the survival, proliferation, and differentiation of hematopoietic cells.

In summary, stromal cells in the bone marrow contribute to the microenvironment and support the functions of hematopoietic cells. They provide structural support, regulate niche signaling, produce extracellular matrix components, engage in cell-cell interactions, and play roles in immune modulation and hematopoietic support.

Yellow marrow is mainly composed of adipocytes (fat cells) and has a reduction in vascularity, which give it a yellowish appearance. It has a higher proportion of fat cells compared to red marrow. Yellow marrow has minimal hematopoietic activity, meaning it produces a significantly lower number of blood cells compared to red marrow. It contains fewer hematopoietic cells and has a less active microenvironment for blood cell production. Yellow marrow is present in the central cavities of long bones, such as the femur and humerus, as well as in the medullary cavity of other bones. Yellow marrow serves as an energy reserve and contributes to overall fat metabolism in the body. It provides insulation and cushioning within the bone cavities. In certain circumstances, such as increased demand for blood cell production or in response to certain pathological conditions, yellow marrow can convert back to red marrow. This is known as reconversion or reactivation of hematopoiesis.

Ratio of Red Marrow to Yellow Marrow It’s important to note that while red marrow is the primary site of hematopoiesis in healthy adults, the distribution and ratio of red to yellow marrow can vary among individuals and throughout different stages of life. With age, red marrow undergoes a physiological transformation into yellow marrow, reducing its hematopoietic activity and becoming progressively replaced by adipose (fat) cells. A rough guide to evaluate normal concentrations of red marrow to yellow marrow is to use the individual’s age (+/- 10%) as the concentration of yellow marrow. The residual will be red marrow. For examples:

• Healthy 10-year old should have 80% - 100% red marrow and 0% - 20% yellow marrow
• Healthy 70-year old should have 60% - 80% yellow marrow and 20% - 40% red marrow

1.1.3 Cell Development

The process of hematopoiesis involves the differentiation and maturation of hematopoietic stem cells (HSCs). HSCs are multipotent cells that have the ability to give rise to all types of blood cells (ie RBCs, WBCs, PLTs). They reside in the bone marrow and undergo a series of steps to produce fully mature blood cells.

The stages involved in hematopoiesis:

1. Pluripotent Stem Cells: Hematopoiesis begins with pluripotent stem cells, which are undifferentiated cells capable of differentiating into various cell types, including self-replication. These cells give rise to both myeloid and lymphoid lineages.

2. Commitment and Differentiation: Pluripotent stem cells differentiate into multipotent progenitor (MPP) cells. These progenitor cells are committed to either the myeloid or lymphoid lineage.

   • Myeloid Lineage: In the myeloid lineage, MPPs differentiate further into common myeloid progenitor (CMP) cells. CMPs give rise to specific progenitor cells for various blood cell types, such as erythrocyte progenitor cells (which develop into RBCs), granulocyte/monocyte progenitor cells (which develop into WBCs), and megakaryocyte progenitor cells (which develop into PLTs).
   • Lymphoid Lineage: In the lymphoid lineage, MPPs differentiate into common lymphoid progenitor (CLP) cells. CLPs give rise to the progenitor cells for lymphocytes, including B cells, T cells, and natural killer (NK) cells.

The process of hematopoiesis is tightly regulated by various growth factors, cytokines, and hormones. For example, erythropoietin (EPO) stimulates the production of erythrocytes, while granulocyte colony-stimulating factor (G-CSF) promotes the development of granulocytes.

1.2 Conclusion

Hematopoiesis is a dynamic and continuous process that ensures the replenishment of blood cells throughout an individual’s life. It is crucial for maintaining a healthy immune system and the proper functioning of oxygen transport (via RBCs), blood clotting (via PLTs), and defense against infections (via WBCs).