Bone marrow is a semi-solid tissue found within the spongy (also known as cancellous) portions of bones. In birds and mammals, bone marrow is the primary site of new blood cell production (or haematopoiesis). It is composed of hematopoietic cells, marrow adipose tissue, and supportive stromal cells. In adult humans, bone marrow is primarily located in the ribs, vertebrae, sternum, and bones of the pelvis. Bone marrow comprises approximately 5% of total body mass in healthy adult humans, such that a person weighing 73 kg (161 lbs) will have around 3.7 kg (8 lbs) of bone marrow.
Human marrow produces approximately 500 billion blood cells per day, which join the systemic circulation via permeable vasculature sinusoids within the medullary cavity. All types of hematopoietic cells, including both myeloid and lymphoid lineages, are created in bone marrow; however, lymphoid cells must migrate to other lymphoid organs (e.g. thymus) in order to complete maturation.
Bone marrow transplants can be conducted to treat severe diseases of the bone marrow, including certain forms of cancer such as leukemia. Several types of stem cells are related to bone marrow. Hematopoietic stem cells in the bone marrow can give rise to hematopoietic lineage cells, and mesenchymal stem cells, which can be isolated from the primary culture of bone marrow stroma, can give rise to bone, adipose, and cartilage tissue.
Structure The composition of marrow is dynamic, as the mixture of cellular and non-cellular components (connective tissue) shifts with age and in response to systemic factors. In humans, marrow is colloquially characterized as red bone marrow, or yellow bone marrow ( and , respectively) depending on the prevalence of hematopoietic cells vs fat cells. While the precise mechanisms underlying marrow regulation are not understood, compositional changes occur according to stereotypical patterns. For example, a newborn baby's bones exclusively contain hematopoietically active red marrow, and there is a progressive conversion towards yellow marrow with age. In adults, red marrow is found mainly in the central skeleton, such as the pelvis, sternum, cranium, ribs, vertebrae and scapulae, and variably found in the proximal epiphyseal ends of long bones such as the femur and humerus. In circumstances of chronic hypoxia, the body can convert yellow marrow back to red marrow to increase blood cell production.
Hematopoietic components
At the cellular level, the main functional component of bone marrow includes the progenitor cells which are destined to mature into blood and lymphoid cells. Human marrow produces approximately 500 billion blood cells per day. Marrow contains hematopoietic stem cells which give rise to the three classes of blood cells that are found in circulation: white blood cells (leukocytes), red blood cells (erythrocytes), and platelets (thrombocytes). + Cellular constitution of the red bone marrow parenchymaAppendix A:IV in Wintrobe's clinical hematology (9th edition). Philadelphia: Lea & Febiger (1993). Group Cell type Average fraction Reference range Myelopoietic cells Myeloblasts 0.9% 0.2–1.5 Promyelocytes 3.3% 2.1–4.1 Neutrophilic myelocytes 12.7% 8.2–15.7 Eosinophilic myelocytes 0.8% 0.2–1.3 Neutrophilic metamyelocytes 15.9% 9.6–24.6 Eosinophilic metamyelocytes 1.2% 0.4–2.2 Neutrophilic band cells 12.4% 9.5–15.3 Eosinophilic band cells 0.9% 0.2–2.4 Segmented neutrophils 7.4% 6.0–12.0 Segmented eosinophils 0.5% 0.0–1.3 Segmented basophils and mast cells 0.1% 0.0–0.2 Erythropoietic cells Pronormoblasts 0.6% 0.2–1.3 Basophilic normoblasts 1.4% 0.5–2.4 Polychromatic normoblasts 21.6% 17.9–29.2 Orthochromatic normoblast 2.0% 0.4–4.6 Other cell types Megakaryocytes < 0.1% 0.0-0.4 Plasma cells 1.3% 0.4-3.9 Reticular cells 0.3% 0.0-0.9 Lymphocytes 16.2% 11.1-23.2 Monocytes 0.3% 0.0-0.8
Stroma The stroma of the bone marrow includes all tissue not directly involved in its primary function of hematopoiesis. Stromal cells support hematopoiesis indirectly by providing a specialized microenvironment that influences the function and differentiation of hematopoietic cells. For example, they produce colony-stimulating factors, which play a significant role in regulating blood cell formation.
Cell types that constitute the bone marrow stroma include: Fibroblasts (reticular connective tissue) Macrophages, which contribute especially to red blood cell production by delivering iron for hemoglobin synthesis Adipocytes (fat cells) Osteoblasts (synthesize bone) Osteoclasts (resorb bone) Endothelial cells, which form the sinusoids. These are derived from endothelial stem cells, which are also present in the bone marrow.
Function
Central hematopoietic and antigen-responsive organ Bone marrow is a priming site for T-cell responses to blood-borne antigens, as first described in 2003. Mature circulating naïve T cells travel to bone marrow sinuses after they have passed through arteries and arterioles. They transmigrate sinus endothelium and enter the parenchyma which contains dendritic cells (DCs). These have a capacity of antigen uptake, processing, and presentation. Cognate interactions between antigen-specific T cells and antigen-presenting DCs (APCs) in parenchyma lead to rapid T-APC cluster formation followed by T cell activation, T cell proliferation and T cell re-circulation to blood. These findings were corroborated and extended in 2013 by in situ two-photon dynamic imaging of mice skulls.
Importance for storage and long-term survival of memory B and memory T cells Bone marrow is a nest for migratory memory T cells and a sanctuary for plasma cells. This has implications for adaptive immunity and vaccinology. Memory B and T cells persist in the parenchyma in dedicated survival niches organized by stromal cells. This memory can be maintained over long time periods in the form of quiescent cells or by repeated antigenic restimulation. Bone marrow protects and optimizes immunological memory during dietary restriction. In cancer patients, cancer-reactive memory T cells can arise in bone marrow spontaneously or after specific vaccination. Bone marrow is a center of a variety of immune activities: i) hematopoiesis, ii) osteogenesis, iii) immune responses, iv) distinction between self and non-self antigens, v) central immune regulatory function, vi) storage of memory cells, vii) immune surveillance of the central nervous system, viii) adaptation to energy crisis, ix) provision of mesenchymal stem cells for tissue repair.
Mesenchymal stem cells
The bone marrow stroma contains mesenchymal stem cells (MSCs), which are also known as marrow stromal cells. These are multipotent stem cells that can differentiate into a variety of cell types. MSCs have been shown to differentiate, in vitro or in vivo, into osteoblasts, chondrocytes, myocytes, marrow adipocytes and beta-pancreatic islets cells.
Bone marrow barrier The blood vessels of the bone marrow constitute a barrier, inhibiting immature blood cells from leaving the marrow. Only mature blood cells contain the membrane proteins, such as aquaporin and glycophorin, that are required to attach to and pass the blood vessel endothelium. Hematopoietic stem cells may also cross the bone marrow barrier, and may thus be harvested from blood.
Lymphatic role The red bone marrow is a key element of the lymphatic system, being one of the primary lymphoid organs that generate lymphocytes from immature hematopoietic progenitor cells.The Lymphatic System. Allonhealth.com. Retrieved 5 December 2011. The bone marrow and thymus constitute the primary lymphoid tissues involved in the production and early selection of lymphocytes. Furthermore, bone marrow performs a valve-like function to prevent the backflow of lymphatic fluid in the lymphatic system.
Compartmentalization Biological compartmentalization is evident within the bone marrow, in that certain cell types tend to aggregate in specific areas. For instance, erythrocytes, macrophages, and their precursors tend to gather around blood vessels, while granulocytes gather at the borders of the bone marrow.
As food
People have used animal bone-marrow in cuisine worldwide for millennia, as in the famed Milanese Ossobuco.Fabricant, Florence. "Begging for Bones: A New Craving for Marrow". The New York Times. 16 September 1998.
Clinical significance
Disease The normal bone marrow architecture can be damaged or displaced by aplastic anemia, malignancies such as multiple myeloma, or infections such as tuberculosis, leading to a decrease in the production of blood cells and blood platelets. The bone marrow can also be affected by various forms of leukemia, which attacks its hematologic progenitor cells. Furthermore, exposure to radiation or chemotherapy will kill many of the rapidly dividing cells of the bone marrow, and will therefore result in a depressed immune system. Many of the symptoms of radiation poisoning are due to damage sustained by the bone marrow cells.
To diagnose diseases involving the bone marrow, a bone marrow aspiration is sometimes performed. This typically involves using a hollow needle to acquire a sample of red bone marrow from the crest of the ilium under general or local anesthesia.
Imaging Medical imaging may provide a limited amount of information regarding bone marrow. Plain film x-rays pass through soft tissues such as marrow and do not provide visualization, although any changes in the structure of the associated bone may be detected. CT imaging has somewhat better capacity for assessing the marrow cavity of bones, although with low sensitivity and specificity. For example, normal fatty "yellow" marrow in adult long bones is of low density (-30 to -100 Hounsfield units), between subcutaneous fat and soft tissue. Tissue with increased cellular composition, such as normal "red" marrow or cancer cells within the medullary cavity will measure variably higher in density.
MRI is more sensitive and specific for assessing bone composition. MRI enables assessment of the average molecular composition of soft tissues and thus provides information regarding the relative fat content of marrow. In adult humans, "yellow" fatty marrow is the dominant tissue in bones, particularly in the (peripheral) appendicular skeleton. Because fat molecules have a high T1-relaxivity, T1-weighted imaging sequences show "yellow" fatty marrow as bright (hyperintense). Furthermore, normal fatty marrow loses signal on fat-saturation sequences, in a similar pattern to subcutaneous fat.
When "yellow" fatty marrow becomes replaced by tissue with more cellular composition, this change is apparent as decreased brightness on T1-weighted sequences. Both normal "red" marrow and pathologic marrow lesions (such as cancer) are darker than "yellow" marrow on T1-weight sequences, although can often be distinguished by comparison with the MR signal intensity of adjacent soft tissues. Normal "red" marrow is typically equivalent or brighter than skeletal muscle or intervertebral disc on T1-weighted sequences.
Fatty marrow change, the inverse of red marrow hyperplasia, can occur with normal aging, though it can also be seen with certain treatments such as radiation therapy. Diffuse marrow T1 hypointensity without contrast enhancement or cortical discontinuity suggests red marrow conversion or myelofibrosis. Falsely normal marrow on T1 can be seen with diffuse multiple myeloma or leukemic infiltration when the water to fat ratio is not sufficiently altered, as may be seen with lower grade tumors or earlier in the disease process.
Histology