In one half of episode 6, Red Blood Cell gets lost once again. This time, she stumbles across the bone marrow where she was born and raised. She remembers back to the time when she was an Erythroblast. One time, she gets lost while running away from a neutrophil pretending to be a bacterium. Separated from the other erythroblasts, she is captured by a real Pseudomonas bacterium. Just as she is about to be killed, Myelocyte appears and tries to fight the bacterium without success. However, this buys time for Macrophage and Neutrophil to arrive and kill the bacterium. Erythroblast thanks Myelocyte for saving her before they part ways.

This blog post will not focus on bone marrow infections as they are relatively rare, save for an open fracture of the bone. Instead, we will focus on how red and white blood cells develop in the bone marrow.

Going deep in the bone marrow

The bone marrow is a soft, spongy tissue found inside bones. They are typically found in the humerus (the upper arm bone) and the femur (upper leg bone). Bone marrow can also be found in flat bones of the hip, ribs, sternum, vertebrae, shoulder blades and skull. Most bone marrow is yellow bone marrow which are typically found in the middle part of bones. Yellow bone marrow is where fats are stored. They are yellow due to the high numbers of adipocytes, cells that store fats.

The red bone marrow is where blood cells are produced. Red bone marrow can be found in spongy bone where it fills the spaces between trabeculae, a network of bone. Inside the red bone marrow is an assortment of cells such as endothelial cells (from blood vessels), osteoblasts (bone-forming cells) and stromal cells which are bound to the extracellular matrix. These cells generate an environment where haematopoietic stem cells (HSCs), blood cell precursors, can proliferate and be exposed to various factors to differentiate into different blood cells. The dividing and sorting of haematopoietic stem cells is akin to the maternity ward shown in the anime.

Did you know? In the human foetus, red blood cells can be produced in other organs such as the liver and spleen. However, by 28 weeks (7 months) of pregnancy, blood cells are solely produced in the bone marrow.

Red blood cell development

Red blood cells are packed with haemoglobin to transport oxygen around the body. However, they cannot divide or repair themselves because they lack a nucleus or organelles to do so. In addition, they only live for around 120 days before they are degraded by macrophages in the spleen. Hence, old red blood cells must be continuously replaced by red blood cells that are produced in the bone marrow. This is mediated by a process called erythropoiesis, where more than 2 million red blood cells are produced per second in a human adult.

In erythropoiesis, haematopoietic stem cells (HSCs) initially differentiate into a common myeloid progenitor (CMP) which can either become a red or white blood cell. It then transforms into a megakaryocyte erythroid progenitor (MEP) which can either become a megakaryocyte (that breaks apart into platelets) or a red blood cell. MEPs that commit to becoming red blood cells form burst-forming unit erythroid (BFU-E) which develop into colony-forming unit erythroid (CFU-E).

Did you know? Erythropoietin (EPO) is an essential factor in erythropoiesis. EPO prevents red blood cell progenitors and erythroblasts from dying, allowing them to mature to red blood cells.

CFU-Es eventually become erythroblasts which develop further in erythroblastic islands. These islands, depicted as classrooms in the anime, consist of erythroblasts surrounding and attaching to a central macrophage (that’s why you see macrophages in the bone marrow in the episode). Erythroblasts undergo several stages as they move away from the centre of the macrophage, from proerythroblasts to basophilic erythroblasts and then polychromatophilic erythroblasts and orthochromatophilic erythroblasts. While in the erythroblastic island, erythroblasts divide into smaller cells, produce proteins (particularly haemoglobin), reduce in size and undergo morphological changes. The macrophage in the erythroblastic island facilitates the development of erythroblasts and also provides iron to enable erythroblasts to produce functional haemoglobin (which require iron to carry oxygen).

Once on the edge of the macrophage, orthochromatophilic erythroblasts undergo enucleation. This involves removing their nucleus and degrading their organelles such as the mitochondria to fit in more haemoglobin. In enucleation, cell proliferation stops and the nucleus is condensed, taken out and cut off from the erythroblast. The freed nucleus is contained in a small cell body called a pyrenocyte that is rapidly engulfed and degraded by the macrophage in the erythroblastic island.

After enucleation, the erythroblast becomes a reticulocyte which undergoes further development in the bone marrow and later the blood stream. Reticulocytes remodel their cell membrane to remove unwanted membrane proteins and reduce in size, expel or degrade remaining organelles and attach structural proteins to the plasma membrane. This transforms the reticulocyte into a mature red blood cell that adopts an elastic, biconcave disc shape to transport oxygen around blood vessels of varying widths.

Neutrophil development

Neutrophils patrol the blood stream, looking for pathogens to eliminate. During infection, neutrophils travel to the infected site where it squeezes through the endothelium to enter tissue. Inside, they engulf and degrade pathogens before dying, becoming part of pus. Regardless of whether an infection is present or not, neutrophils typically only live for a week. Hence, neutrophils need to be continuously replenished in the bone marrow. Given that neutrophils are the most common white blood cells in the blood, it is no surprise that they and their precursors make up 60% of white blood cells in the bone marrow.   

Neutrophils are derived from common myeloid progenitor cells (CMPs), but unlike red blood cells they become granulocyte monocyte progenitor cells (GMPs) which can become a monocyte, a neutrophil, an eosinophil or a basophil. By producing certain factors inside a GMP such as C/EBP-α and C/EBP-ε and repressing others such as PU.1 (a monocyte factor) and GATA-1 (an eosinophil factor), GMPs commit to become a neutrophil. The GMP undergoes many stages, initially becoming a myeloblast and promyelocyte before becoming a myelocyte. From there, it becomes a metamyelocyte and a band neutrophil before transforming into a neutrophil.

While neutrophil progenitors develop into neutrophils, they undergo granulopoiesis to sequentially produce different granules. Granulopoiesis enhances the abilities of neutrophils to kill pathogens and to enter tissue from the bloodstream. In the order in which granules are developed:

1. Azurophilic (primary) granules: these granules contain enzymes, particularly myeloperoxidase (MPO), and antimicrobials to break down pathogens and promote inflammation.
2. Specific (secondary) granules: these granules contain antimicrobials to inhibit pathogen growth and factors that can be secreted to attract white blood cells.
3. Gelatinase (tertiary) granules: these granules contain enzymes that break down the extracellular matrix as the neutrophil rolls and stick to the endothelium on the blood vessel. This allows the neutrophil to migrate through the endothelium to enter infected or inflamed tissue.
4. Ficolin-1-rich granules: these granules contain human structural and cytoskeletal proteins such as human serum albumin, LFA-1 and actin to facilitate neutrophil transmigration and movement in tissue.
5. Secretory vesicles: these vesicles contain cell membrane receptors that are required for neutrophils to migrate from blood vessels and enter infected or inflamed tissue.

Once the neutrophil progenitor becomes a mature neutrophil, they exit the bone marrow by traversing the endothelium and entering the blood stream. From there, it will circulate around the body for infection or tissue damage.

Conclusion

The bone marrow is the sole factory of blood cells in the human body. Here, haematopoietic stem cells proliferate and undergo various stages to become mature blood cells. For red blood cells, they initially form colonies of progenitors before undergoing further development in erythroblastic islands as erythroblasts. After enucleation, they become reticulocytes that undergo further changes to become mature red blood cells. Similar to red blood cells, neutrophils undergo several stages where they produce different granules to become efficient pathogen killers. In short, the bone marrow is very important in maintaining a healthy body not only in keeping red blood cell numbers stable but also in defending against infection.  

Next time, over one-and-a-half episodes, we will look at cancer, how it develops and what the immune system does to eliminate tumour cells. See you then!