Composition of Bone Marrow

Bone marrow, the primary site of hematopoiesis, is found in the cavities of cancellous bones and the medullary canals of long bones. There are 2 types: red marrow (hematopoietic with abundant blood cells) and yellow marrow (predominantly filled with adipocytes). Human marrow composition changes with age. In the young, the entire bone marrow is red, as there is increased blood cell production. As age increases, there is gradual change to the yellow marrow variety. The yellow marrow can revert to red marrow when hematopoiesis is needed (e.g., anemia). The red marrow, by hematopoiesis, produces about 6 billion cells per kilogram per day. The process relies on hematopoietic cells (stem cells and progenitors) producing mature effector cells (lymphocytes, platelets, granulocytes, erythrocytes) with the aid of nonhematopoietic elements. Production is regulated by cytokines released in the bone marrow environment and feedback from target tissues. The marrow structure allows hematopoiesis to take place in the extravascular area, and after staged differentiation, blood cells are released into circulation.

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Overview

Definition

Bone marrow is the spongy tissue found in the medullary canals of long bones and the cavities of cancellous bones. 

  • Primary site of blood cell formation (by the 5th month of gestation):
    • 1st months in utero: the mesoderm of the yolk sac
    • By the 2nd–3rd month: Hematopoiesis moves to the liver (and spleen).
    • By the 5th month: Hematopoiesis occurs in the bone marrow, and the bone marrow eventually becomes the predominant source of blood cells. 
  • Other functions:
    • Breakdown of old RBCs (into bilirubin, iron, globin) via macrophages and reuse of iron
    • Storage of fat through adipocytes
  • Blood cell formation (hematopoiesis) is adjusted according to needs and is necessary as lifespan of cells are limited:
    • WBCs: a few hours to days
    • Platelets: up to 10 days
    • RBCs: 120 days
  • Principal blood supply is from 1 or more nutrient arteries:
    • Penetrate to the medulla of the bone
    • The medullary arteries have radial branches that travel to the inner surface of the cortex and connect to the smaller periosteal arterial supply.
    • From the cortex, capillaries return into the medullary cavity and form a network of sinusoidal systems. 
  • Myelinated and nonmyelinated nerves (entering through the nutrient canals) provide the innervation.
Blood supply in the bone

Image shows the blood supply (artery and vein)

Image: “609 Body Supply to the Bone” by OpenStax College. License: CC BY 3.0

Types of marrow

  • Based on gross examination:
    • Red bone marrow:
      • Hematopoietic/blood-forming
      • Abundant blood cells
      • The level decreases with age.
      • Located in: flat bones (skull, sternum, vertebrae, scapulae, and pelvic bones), epiphysis of long bones (femur, tibia, humerus)
    • Yellow bone marrow:
      • Nonhematopoietic
      • Filled with adipocytes
      • The level increases with age.
      • Located in the diaphysis of the long bones
  • Differences and development: 
    • In the newborn, the entire bone marrow is red and is active in blood cell production.
    • As age increases, there is a gradual change to the yellow marrow variety. 
    • In certain conditions (severe bleeding, anemia, or hypoxia), yellow marrow reverts to red.

Bone Marrow Cells and Structures

Hematopoietic

  • Hematopoietic stem cells (HSCs): 
    • Multipotent cells with ability to self-renew and differentiate to all hematopoietic lineage cells
    • HSCs are in close association with the bone-lining cells.
  • Multipotent progenitor (MPP) cells:
    • HSCs progress to MPP cells.
    • Non-self-renewing but with potential for full-lineage differentiation
  • Oligopotent progenitors:
    • MPP cells further develop downstream into oligopotent progenitors:
      • Common lymphoid progenitors (CLPs)
      • Common myeloid progenitors (CMPs)
    • CMPs and CLPs develop into lineage-restricted progenitors and, through stages, eventually become effector cells or differentiated cells:
      • Granulocytes: with secretory granules in the cytoplasm (eosinophils, neutrophils, basophils)
      • Monocytes: differentiate into macrophages
      • Megakaryocytes: become platelets
      • Erythrocytes or RBCs: oxygen-carrying, biconcave cells without nucleus
      • CLP → lymphocytes
    • Mature cells are in the perisinusoidal area.

Nonhematopoietic

Structures that provide a microenvironment that supports the differentiation of hematopoietic cells and proliferation of blood cells:

  • Bone cells: 
    • Provide support to the bone marrow
    • Endosteal lining: layer of flat cells in the inner surface of the bone cavities
    • Osteoclasts and osteoblasts are found in the lining.
  • Marrow stroma:
    • Does not participate in the process of hematopoiesis but provides growth factors/cytokines
    • Formed by stromal or reticular cells, macrophages, and the extracellular matrix in the extravascular space
    • Adipocytes support late-stage (not progenitor-stage) myeloid and lymphoid cells and are for storage of fat/lipid.
  • Sinusoids (lined with endothelial cells):
    • Hematopoiesis occurs in the extravascular spaces.
    • Sinusoids provide a barrier between the circulation and the hematopoietic process, preventing release of immature blood cells from the bone marrow.
    • Differentiated blood cells pass through the blood vessel endothelium by transcellular migration and go into circulation.

Hematopoiesis

Production of blood cells

Hematopoiesis starts with an HSC, which is prompted to divide and differentiate with appropriate chemical stimuli (hemopoietic growth factors).

  • Lymphoid stem cells give rise to lymphocytes:
    • T cells
    • B cells
    • Natural killer (NK) cells
  • Myeloid stem cells eventually differentiate into platelets, erythrocytes, granulocytes, and monocytes:
    • IL-3 stimulates the differentiation of multipotent HSCs into myeloid progenitor cells.
    • Granulocyte macrophage colony-stimulating factor (GM-CSF) → differentiation from myeloid progenitors to granulocytes (neutrophils) and monocytes 
    • IL-5 → differentiation to eosinophils
    • Thrombopoietin (TPO) → differentiation to thrombocytes (platelets)
    • EPO → differentiation to erythrocytes (RBCs)
Bone marrow hematopoiesis

Bone marrow hematopoiesis: proliferation and differentiation of the formed elements of blood
CFU-GEMM: colony-forming unit: granulocyte, erythrocyte, monocyte, megakaryocyte
CFU-GM: colony-forming unit: granulocyte-macrophage
GM-CSF: granulocyte-macrophage colony-stimulating factor
M-CSF: macrophage colony-stimulating factor
G-CSF: granulocyte colony-stimulating factor
NK: natural killer
TPO: thrombopoietin

Image by Lecturio. License: CC BY-NC-SA 4.0

Major hematopoietic growth factors

Table: Major hematopoietic growth factors
Cytokines/growth factorsActivitiesSource
Erythropoietin (EPO)Stimulates erythropoiesis, including differentiation
  • Kidney
  • Liver
Thrombopoietin (TPO)Stimulates thrombopoiesis
  • Kidney
  • Liver
Stem cell factor (SCF)Stimulates all hematopoietic progenitor cellsBone marrow stromal cells
Granulocyte-macrophage colony-stimulating factor (GM-CSF)Stimulates myeloid progenitor cells
  • Endothelial cells
  • T cells
Granulocyte colony-stimulating factor (G-CSF)Stimulates neutrophil precursor cells
  • Endothelial cells
  • Macrophages
Monocyte colony-stimulating factor (M-CSF)Stimulates monocyte precursor cells
  • Endothelial cells
  • Macrophages

Interleukins

Table: Interleukins
Interleukin (IL)ActivitiesSource
IL-1Regulation of cytokine secretion of many leukocytes
  • Macrophages
  • T helper cells
IL-2
  • Mitogen for activated T and B cells
  • Differentiation of NK cells
T helper cells
IL-3Mitogen for all granulocyte and megakaryocyte/erythrocyte progenitor cellsT helper cells
IL-4
  • Development of basophils and mast cells
  • Activation of B-lymphocyte
T helper cells
IL-5Development and activation of eosinophilsT helper cells
IL-6
  • Mitogen for leukocytes
  • Activation of B cells and regulatory T cells
  • Macrophages
  • Neutrophils
  • Endothelial cells
IL-7Stimulation of all lymphoid stem cellsStromal cells of bone marrow

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Clinical Relevance

  • Thrombocytopenia: describes a deficiency in thrombocytes in peripheral blood. Thrombocytes or platelets are functionally integrated into the hemostasis system. Thus, thrombocyte function disorders cause pathological bleeding. In the spectrum of hemorrhagic diatheses, thrombocytopenia is the main cause of pathological bleeding.
  • Anemia: decrease in total number of RBCs, hemoglobin, or circulating RBC mass. Anemia is usually reflected in decreased hemoglobin and hematocrit and can arise from reduced hematopoiesis, hemolysis, or blood loss.
  • Acute lymphoblastic leukemia (ALL): the most common form of cancer affecting children, characterized by uncontrolled proliferation of lymphoid precursor cells (increased lymphoblasts). Normal marrow is replaced by lymphoblasts, which go into circulation and infiltrate other organs. The signs and symptoms of ALL are related to anemia, thrombocytopenia, and lack of functional WBCs. Peripheral blood smear and bone marrow biopsy examination show lymphoblasts. Immunophenotyping, histochemistry, and genetic studies aid in diagnosis and treatment.
  • Acute myeloid leukemia (AML): a hematologic malignancy characterized by uncontrolled proliferation of myeloid precursor cells (increased myeloblasts). The condition is seen predominantly in older adults. Replacement of normal marrow by malignant cells occurs, leading to impaired hematopoiesis. Clinical presentation is related to anemia, thrombocytopenia, and lack of functional WBCs. Diagnosis is via peripheral blood smear and bone marrow biopsy examination showing myeloblasts. The precursor cells contain Auer rods. 
  • Chronic myeloid leukemia: malignant proliferation of the granulocytic cell line, with a fairly normal differentiation. The underlying genetic abnormality is the Philadelphia chromosome. The chromosome contains the BCR-ABL1 fusion gene, which produces constitutive tyrosine kinase activation, leading to uncontrolled granulocytic production. Elevated WBC and a peripheral smear with increased numbers of immature cells are seen. Philadelphia chromosome demonstration by cytogenetic techniques is considered the gold standard diagnostic test. 
  • Chronic lymphocytic leukemia (CLL): a slowly growing blood and bone marrow cancer characterized by excess production of monoclonal B lymphocytes in the peripheral blood. When the involvement is primarily nodal, the condition is called small lymphocytic lymphoma (SLL). The disease usually presents in older adults, with a median age of 70 years. Often, with asymptomatic presentation, diagnosis is made when abnormal lymphocytosis is seen on laboratory testing. Cytopenias can also be seen. The B cells are functionally incompetent lymphocytes and thus may result in recurrent infections. 

References

  1. Mescher, AL. (Ed.). (2021). Hemopoiesis. Junqueira’s Basic Histology Text and Atlas, 16e. McGraw-Hill. https://accessmedicine.mhmedical.com/content.aspx?bookid=3047&sectionid=255121548
  2. Panchbhavi, V. (2017). Bone marrow anatomy. Medscape. Retrieved June 20, 2021, from https://emedicine.medscape.com/article/1968326-overview#a1
  3. Paulsen, DF. (Ed.). (2010). Hematopoiesis. Histology & Cell Biology: Examination & Board Review, 5e. McGraw-Hill. https://accessmedicine.mhmedical.com/content.aspx?bookid=563&sectionid=42045308
  4. Seita, J, Weissman, IL. (2010). Hematopoietic stem cell: Self-renewal versus differentiation. Wiley interdisciplinary reviews. Systems biology and medicine. 2(6), 640–653. https://doi.org/10.1002/wsbm.86

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