Histology of Bone MarrowThe bony skeleton that supports the human body and facilitates locomotion has an intricate microarchitecture of its own. The cavities created by the trabecular arrangement of the core of the bones are occupied by a mixture of blood cells across a large spectrum of development, and adipocytes. This tissue is known as bone marrow and is responsible for the production of blood cells – a process known as hematopoiesis.
This article will review the embryology of the bone marrow as well as its histology. Additionally, the constituent cell lineages and their function will be discussed, together with clinically relevant processes and pathologies.
Haematopoietic stem cells arise from mesodermal cells that have been stimulated by fibroblast growth factor 2 (FGF2). FGF2 binds to the fibroblast growth factor receptors (FGFR), inducing the conversion of mesodermal cells into hemangioblast cells that reside in the yolk sac wall of the developing embryo. Hemangioblasts serve as stem cells for both vascular and haematopoietic cells. In the presence of vascular endothelial growth factor (VEGF), hemangioblast cells differentiate into vascular endothelium. The undifferentiated hemangioblasts will subsequently participate in either angiogenesis (formation of blood vessels from existing blood vessels) or haematopoiesis (formation of blood cells) depending on whether they are peripherally or centrally located, respectively.
Although the haematopoietic process outlined above begins around the second to third gestational week, active haematopoiesis does not commence in the bone marrow until the 10th – 11th gestational week. Recall that bone marrow occupies the central region of bone. Therefore, the formation of bone marrow is dependent on the development of trabecular bone. Loosely arranged mesenchymal cells suspended in a dense thread-like network of fibrils, all encircling a central artery, come together to form primary logettes. Cluster of differentiation 15 positive (CD15+) myeloid cells and glycophorin A positive cells are among the first cell lines to be produced in the marrow. It should also be noted that primary logettes are located as far as possible from areas of ossification.
Gross Anatomy & Histology
Types of Bone Marrow
Bone marrow lacks the rigidity of the surrounding bone. Instead, it is a jelly-like substance that fills the cavity left by the trabecular network of bone. Bone marrow accounts for about 4 – 5% of the total body weight of an individual. Although it can be considered a “light-weight” system, the bone marrow does a lot of heavy lifting, as it is responsible for producing platelets, lymphocytes, erythrocytes, granulocytes, and monocytes.
Marrow has two principal functions; one is to produce blood cells and the other is to store fat. As a result, there are two types of marrow found in the body:
- the highly vascular red marrow which is haematopoietically active,
- and the fat rich yellow marrow that has significantly less haematopoietic centres and more adipocytes.
Red Bone Marrow
Clusters of haematopoietic cells known as haematopoietic islands are widely distributed throughout the loose connective tissue network observed in red marrow. These islands are found next to relatively large, yet thin walled, sinusoids that also communicate with nutrient vessels of the bone. The sinusoids are situated at a central part of a roundabout circulation such that the nutrient arteries that leave the nutrient canals to supply the bones anastomose in the bone marrow and subsequently terminate in arterioles that coalesce to form the sinusoids. The sinusoids then drain to significantly larger veins that form nutrient veins, which then leave the bone via the same nutrient canals that the arteries enter by.
Red marrow is most abundant in all skeletal structures from intrauterine life up until around the 5th year of life. As time progresses, red marrow is restricted to the central flat bones (i.e. cranial bones, clavicle, sternum, ribs, scapula, vertebrae, and pelvis) and the proximal ends of the proximal long bones of the upper and lower limbs.
The supporting substance that supports the haematopoietic and adipocyte cells in the marrow is made up of reticulin. This is a fine type III collagen that is produced by mesenchyme derived reticular cells (fibroblast-like cells). Other housekeeping cells like macrophages exist in the stroma and facilitate haematopoiesis by phagocytosing cellular debris generated from the process.
Yellow Bone Marrow
Depending on the age and haematological demand of an individual, the reticular cells become swollen as a result of increased lipid uptake. Subsequently, yellow marrow is formed. It contains mainly supportive connective tissue that provides scaffolding for the neurovascular structures that traverse the cavitation. There are also numerous adipocytes in addition to very few dormant haematopoietic clusters. These latent haematopoietic centres can be reactivated in the event of an increase demand for red blood cells.
The bone marrow is perfused by the same arteries that provide nutrients to the surrounding bone. A nutrient artery and two nutrient veins travel through nutrient canals to enter the bone marrow. The nutrient artery bifurcates after entering the marrow; each artery travels along the long axis of the bone in opposite directions. The vessels are tortuous in their course around the central longitudinal vein and venous marrow channels.
The artery subsequently arborizes to supply the bony cortex. However, some of these thin-walled arterioles and their subsequent capillaries anastomose with venous sinus plexuses. The plexuses are tributaries to the collecting venules, which also drain to the central longitudinal vein. The central longitudinal vein then returns newly formed blood cells from the marrow pool to the systemic circulation. Presently, no lymphatic channels within the marrow cavity have been identified.
The nutrient canals – as well as both epiphyseal and metaphyseal foramina – also carry both unmyelinated and myelinated nerve fibres to the bone; and by extension, the marrow. Some of these fibres serve as vasa nervosa – innervating the smooth muscle layer of the blood vessels – as well as the haematopoietic tissue of the marrow.
Histological analysis of the bone marrow will reveal an abundance of progenitor cells and their derivatives at different stages of development. Typically, the progenitor cells are larger than their end products. The suffix “-blast” is often used to denote that the cell line being referenced are the stem cells for that series (i.e. erythroblasts are the precursor cells for red blood cells [erythrocytes]). The following is a list of the cell lines found in the bone marrow:
- Granulocytes – are a special line of white blood cells that possess secretory granules in their cytoplasm. There are three granulocytes; these are eosinophils, basophils and neutrophils.
- Monocytes – are leukocytes that differentiate into macrophages. Recall that there are different subtypes of macrophages depending on the region of the body that they are found in (i.e. Kupffer cells of the liver).
- Erythrocytes – are the anucleate, biconcave, oxygen-carrying species.
- Megakaryocytes – is another large species that is responsible for thrombocytogenesis (i.e. platelet production).
- Lymphocytes – are all produced in the bone marrow. However, education and maturation of one subset of lymphocytes occurs in the thymus (i.e. T-lymphocytes).
The stroma also contains a myriad of stem cells of mesenchymal origin. These include multipotent cell lines that are capable of differentiating into cartilaginous cell lines (chondrocytes), bone cells (osteoblasts and osteoclasts) in addition to adipocytes, myocytes (muscle) and endothelial cells.
Bone Marrow Aspiration & Biopsy
Haematopoiesis is important not only for the maintenance of metabolism (i.e. production of red blood cells that carry oxygen) but also for the sustenance of the immune system (i.e. leukogenesis). Both pathological and physiological states can affect the status of the bone marrow such that the marrow can become hypercellular or hypocellular. The cellularity of the bone marrow refers to the quantity of haematopoietic cells with respect to the adipocyte composition.
In order to adequately assess the composition of the bone marrow, clinicians perform either a bone marrow biopsy or bone marrow aspiration. Both procedures allow for acquisition of red marrow that can be decalcified and processed for histological assessment. The process is historically referred to as trepanning (surgically drilling holes in the skull for therapeutic benefits). Marrow aspiration involves introducing a large bore needle into the bone marrow percutaneously, using a sterile technique. The resulting sample is ideal for cytological analysis. The biopsy procedure would permit a larger sampling of the marrow and by extension, greater assessment of the marrow cellularity. More importantly, biopsy increases the likelihood of detecting and sampling focal insults, as well as assessing the degree of damage caused by the lesion. Furthermore, obtaining a bone marrow biopsy allows for the clinician to have an understanding of the overall marrow architecture outside of the intratrabecular space. Both diagnostic and therapeutic indications exist for bone marrow aspiration and biopsy.
The following are relative indications for conducting a bone marrow aspiration or biopsy:
It is ideal for investigation of depletion of any or all of the cell lines (i.e. leukopenia , myelodysplasia, thrombocytopenia or anaemia).
Conversely, the aetiology of an otherwise unexplainable abnormal increase in any of the cell lines can also be investigated with this modality.
A rationale for morphological discrepancies can be ascertained (i.e. rouleaux formation, leucoerythroblastic picture, or teardrop erythrocytes).
It is useful in monitoring disease progression and the response to therapy.
Clinicians can also see whether or not the marrow is involved with metastatic neoplasms.
Albeit not a first line option in this scenario, it can be included as part of the investigation panel for a patient with a fever of unknown origin as well as those with unexplainable enlargement of secondary lymphoid tissue (i.e. hepatomegaly and lymphadenopathy).
Bone Marrow Suppression
It is possible that extensive lesions within the bone marrow can lead to a decrease in the marrow activity. However, the aetiological factors resulting in bone marrow suppression can often be iatrogenic in response to chemotherapeutic agents being used to manage an underlying neoplastic entity. It is likely that this marrow suppression may result in a pancytopenia (fall in all cell lines).
The decreased cell lines will predispose the patient to anaemia (decreased erythroid line), infections (decreased myeloid lines), and increased risk of bleeding (thrombocytopenia). Common drugs that may lead to marrow suppression include (but are not limited to) – methotrexate, azathioprine, non-steroidal anti-inflammatory drugs, cyclophosphamide, and other cytotoxic drugs.
Bone Marrow Failure
In more severe cases, the bone marrow can be immensely affected by disease processes where it is unable to produce one or all of the cell lines (i.e. a pancytopenia). This syndrome is referred to as bone marrow failure. It can be congenital (i.e. Fanconi’s anaemia or dyskeratosis congenital) or acquired (aplastic anaemia or chemotherapeutic drugs). There are at least three points in the cellular assembly line that are important in understanding bone marrow failure:
An insult to the haematopoietic stem cells or the environment that supports their replication can eventually lead to a decline in the bone marrow’s ability to make more cells. If there are no progenitor cells, then there is nothing for the cell lines to differentiate from.
Nutrient deficiencies can also impact the marrow’s ability to produce cells. For example, severe folate and B12 deficiencies will initially result in a megaloblastic picture. However, when these vitamins are depleted, then the process of DNA replication – and by extension, cellular reproduction – will cease.
Finally, the first two steps may be functioning correctly, but there is a problem with differentiation of the cell lines (as observed in myelodysplastic disorders).