Hematopoiesis: Blood Cell Development

• Hematopoiesis refers to the development of red blood cells (erythropoiesis), white blood cells (leukopoiesis), and platelets (thrombopoiesis).
• The goal of hematopoiesis is to maintain a constant level of different cell types in the blood due to their limited life span.
• Erythrocytes and platelets spend their entire life in circulating blood.
• Leukocytes migrate out of the circulation shortly after entering from the bone marrow and spend most of their life spans in the tissues.
• In adults, blood cells are created from hemopoietic stem cells (HSCs) in the bone marrow.
• HSCs differentiate into common myeloid progenitor (CMP) cells and common lymphoid progenitor (CLP) cells under the influence of cytokines and growth factors.
• CMP cells give rise to megakaryocytes (platelets), erythrocytes, neutrophils, eosinophils, basophils, mast cells, and monocytes (macrophages).
• CLP cells give rise to T cells, B cells, and NK cells.
• Hemopoietic stem cells are also called pluripotential stem cells (PPSC).
• Progenitor cells differentiate into another cell type, eventually changing into their specific target cell type.
• Hemopoietic stem cells can change into many different cell types.

Differentiation of Common Myeloid Progenitor (CMP) Cells

• CMP cells differentiate into Megakaryocyte-Erythrocyte Progenitor (MEP) cells and Granulocyte-Monocyte Progenitor (GMP) cells.

Megakaryocyte-Erythrocyte Progenitor (MEP) Cells:

• MEP cells give rise to megakaryocyte progenitor cells (MKP) that become megakaryocytes and then platelets.
• MEP cells give rise to erythrocyte progenitor cells (ErP) that become erythrocytes (red blood cells).

Granulocyte-Monocyte Progenitor (GMP) Cells:

• GMP cells give rise to neutrophil progenitors (NoP) that become neutrophils.
• GMP cells give rise to eosinophil progenitors (EoPs) that become eosinophils.
• GMP cells give rise to Basophil-Mast Cell Progenitors (BMCPs) that become basophils and mast cells.
• GMP cells give rise to monocyte progenitors (MoP) that become monocytes and then macrophages.
• GMP cells give rise to pro-dendritic cells that become dendrites.

Common Lymphoid Progenitor (CLP) Cells:

• CLP cells differentiate into T cells, B cells, and NK cells.

Control of Differentiation

• Transcription factors and hematopoietic cytokines control differentiation, such as what makes a stem cell create neutrophils versus monocytes.

Transcription Factors:

• Transcription factors bind to specific regions of a cell's DNA to control gene transcription, triggering genetic changes that determine cell fate during differentiation.

Hematopoietic Cytokines:

• Hematopoietic cytokines are glycoproteins that circulate and regulate hematopoiesis and the rate of differentiation of different cell types, acting primarily on progenitor cells.
• The types of hematopoietic cytokines include colony-stimulating factors (CSFs), interleukins, interferons, and select hormones.
• CSFs include granulocyte–macrophage colony-stimulating factor (GM-CSF), granulocyte colony-stimulating factor (G-CSF), and monocyte colony-stimulating factor (M-CSF).
• Hormones include erythropoietin and thrombopoietin.
• Interleukins include IL1 – IL 13, produced by leukocytes, endothelial cells, bone marrow cells, osteoblasts, and dendritic cells.

Development of Granulocytes (Granulopoiesis)

• Granulopoiesis takes about 2 weeks in the bone marrow.
• Granulocytes originate from the common myeloid progenitor (CMP) stem cell.
• The CMP cell differentiates into Granulocyte-Monocyte Progenitor (GMP) cells under the influence of GM-CSF, G-CSF, and IL-3.
• G-CSF is secreted by endothelial cells, T cells, macrophages, mast cells, and fibroblasts.
• GMP cells then produce neutrophils, eosinophils, and basophils and monocytes.

Neutrophils:

• GMP cell → NoP cell → myeloblast → promyelocyte → neutrophilic myelocyte → neutrophilic metamyelocyte → band → neutrophil.
• Bone marrow produces more than 10^11 neutrophils each day.
• Mature neutrophils are stored in the bone marrow for 4–6 days.
• Neutrophils can be rapidly mobilized from the bone marrow in under 1 hour in response to tissue injury or infection.
• Inflammatory cytokines, such as G-CSF, IFN-α, and IFN-γ, induce the release of neutrophils from the bone marrow.
• Neutrophils circulate for a few minutes to 16 hours before entering the tissue.
• Neutrophils live for 1–2 days in the connective tissue.
• As they age, neutrophils are destroyed by apoptosis in the bone marrow, liver, and spleen and are engulfed by macrophages.

Eosinophils:

• GMP cell → EoP cell → myeloblast → promyelocyte → eosinophilic myelocyte → eosinophilic metamyelocyte → eosinophil.

Basophils:

• GMP cell → BaP cell → myeloblast → promyelocyte → basophilic myelocyte → basophilic metamyelocyte → basophils.

Stages of differentiation:

• Myelocytes exhibit granules.
• The metamyelocyte stage is when distinct cell lines can be differentiated (neutrophils, eosinophils, basophils).

Monocytes:

• GMP cell → MoP cell → Monoblast → Promonocyte → Monocyte.
• It takes abut 55 hours for the MoP cell to transform into the monocyte.
• Monocytes remain in the circulation for about 16 hours before emigrating to the tissues where they differentiate into tissue macrophages.
• GM-SCF and M-CSF stimulate this transformation.

Development of Lymphocytes (Lymphopoiesis)

• Lymphopoiesis refers to the formation of agranular nucleocytes that mature or reside in peripheral lymphoid tissue.
• The major types of lymphoid cells are T-lymphocytes and B-lymphocytes.
• All lymphocytes originate in the bone marrow.

T-Lymphocytes:

• CLP cell → pre-T lymphocytes.
• Pre-T lymphocytes migrate from the bone marrow to the thymus, completing differentiation and “thymic cell education” before entering circulation as long-lived T lymphocytes.

B-Lymphocytes:

• CLP cell → B lymphocytes.
• B lymphocytes either stay in the bone marrow or migrate to the lymphatic tissue in the GI tract or the spleen.

NK Cells:

• CLP cell → pre-NK cells.
• Remain in the bone marrow where they become mature NK cells.

Development of Erythrocytes (Erythropoiesis)

• Erythropoiesis occurs in the bone marrow.
  • Hematopoietic stem cell (HSC).
  • Gives rise to the Common Myeloid Progenitor Cell (CLP) under stimulation from PU.1 transcription factor.
  • Gives rise to the Megakaryocyte-Erythrocyte Progenitor (MEP) cell.
  • Gives rise to the erythrocyte progenitors (ErPs).
  • Give rise to the proerythroblast.
  • Gives rise to the orthochromatic erythroblast where the nucleus is extruded.
  • Gives rise to the reticulocyte that hangs out in the bone marrow for ~24 hours before exiting to the circulation; after ~24 hours in circulation, these cells enter the spleen to mature into erythrocytes.

Development of Thrombocytes (Thrombopoiesis)

• Daily production in the bone marrow of a healthy adult is about 1 × 10^11 platelets (can increase 10-fold in demand).
• Thrombocytopoiesis requires support of ILs, CSFs, and hormones.
  • Common Myeloid Progenitor Cells (CMP) → Megakaryocyte-Erythrocyte Progenitor (MEP) cell, which occurs under influence of granulocyte–macrophage colony-stimulating factor (GM-CSF) and IL-3.
  • Becomes a Megakaryocyte-committed progenitor (MKP) cell.
  • Becomes a megakaryoblast → promegakaryocyte → megakaryocyte.
• The megakaryocyte undergoes multiple rounds of endomitosis under the influence of thrombopoietin.
• Endomitosis is a process in which the chromosomes of the cell divide but the cell does not then undergo nuclear division, increasing the ploidy of the cell from 8n to 64n before chromosomal replication ceases.
• The cell then becomes a platelet-producing megakaryocyte.
• The plasma membrane invaginates and divides the cytoplasm into small cells of cytoplasm surrounded by a plasma membrane, forming platelets.

Definitions:

• Differentiate: to make or become different in the process of growth or development; differentiation is this process.
• Cytokines: Small proteins produced by a wide variety of cells that act as “cell signalers" to direct the activities of other cells.
• Glycoproteins: Proteins that have carbohydrate groups attached to the polypeptide chain.
• Progenitor cells: Cells that differentiate into another cell type; will only differentiate into one specific target cell.
• Lymphatic tissues: An organ system that is part of the immune system with components including lymphatic vessels, lymph nodes, spleen, thymus, and lymph.
• Lymph: A clear fluid carried by the lymphatic vessels from throughout the body back to the heart for re-circulation.
• Myeloid: Tissue of bone marrow, tissue of bone marrow cell lineage, tissue arising from bone marrow.
• Lymphoid: Tissue responsible for producing lymphocytes and antibodies.

Hematopoiesis is the process of blood cell development, including erythrocytes, leukocytes, and platelets. Hematopoietic stem cells (HSCs) in the bone marrow differentiate into myeloid and lymphoid progenitor cells. These progenitors then develop into the various blood cell types.