Bone marrow

Bone marrow is a semi-solid tissue found within the spongy portions of bones. In birds and mammals, bone marrow is the primary site of new blood cell production. 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 will have around 3.7 kg 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 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 shifts with age and in response to systemic factors. In humans, marrow is colloquially characterized as red bone marrow, or yellow bone marrow 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, red blood cells, and platelets.

Group	Cell type	Average fraction	Reference range
Myelopoietic cells	Myeloblasts	0.9%	0.2–1.5
Myelopoietic cells	Promyelocytes	3.3%	2.1–4.1
Myelopoietic cells	Neutrophilic myelocytes	12.7%	8.2–15.7
Myelopoietic cells	Eosinophilic myelocytes	0.8%	0.2–1.3
Myelopoietic cells	Neutrophilic metamyelocytes	15.9%	9.6–24.6
Myelopoietic cells	Eosinophilic metamyelocytes	1.2%	0.4–2.2
Myelopoietic cells	Neutrophilic band cells	12.4%	9.5–15.3
Myelopoietic cells	Eosinophilic band cells	0.9%	0.2–2.4
Myelopoietic cells	Segmented neutrophils	7.4%	6.0–12.0
Myelopoietic cells	Segmented eosinophils	0.5%	0.0–1.3
Myelopoietic cells	Segmented basophils and mast cells	0.1%	0.0–0.2
Erythropoietic cells	Pronormoblasts	0.6%	0.2–1.3
Erythropoietic cells	Basophilic normoblasts	1.4%	0.5–2.4
Erythropoietic cells	Polychromatic normoblasts	21.6%	17.9–29.2
Erythropoietic cells	Orthochromatic normoblast	2.0%	0.4–4.6
Other cell types	Megakaryocytes	< 0.1%	0.0-0.4
Other cell types	Plasma cells	1.3%	0.4-3.9
Other cell types	Reticular cells	0.3%	0.0-0.9
Other cell types	Lymphocytes	16.2%	11.1-23.2
Other cell types	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
Macrophages, which contribute especially to red blood cell production by delivering iron for hemoglobin synthesis
Adipocytes
Osteoblasts
Osteoclasts
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

That bone marrow is a priming site for T-cell responses to blood-borne antigens was first described in 2003. Mature circulating naïve T cells home to bone marrow sinuses after they have passed through arteries and arterioles. They transmigrate sinus endothelium and enter the parenchyma which contains dendritic cells. These have a capacity of antigen uptake, processing, and presentation. Cognate interactions between antigen-specific T cells and antigen-presenting DCs 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, 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 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

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.

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.