Leukopoiesis

Leukopoiesis pathway

Introduction

Leukopoiesis is the process of formation of leukocytes (white blood cells) from stem cells in haematopoietic organs. Leukocytes develop from either multipotential myeloid stem cells (CFU-GEMM) or multipotential lymphoid stem cells (CFU-L).

Leukocytes developing from CFU-GEMM’s are granulocytes (neutrophils, basophils and eosinophils) or monocytes. Leukocytes developing from CFU-Ls are lymphocytes (T & B cells, dendritic and NK cells).

Granulopoiesis

All granulocytes develop from the CFU-GEMM cells.

Summary of pathways

	Monocyte	Neutrophil	Basophil	Eosinophil	©RVC 2008
Stem cell	CFU-GEMM
CFU	CFU-M	CFU-G	CFU-Ba	CFU-Eo
Cytokines	GM-CSF IL-3 M-CSF	GM-CSF IL-3 G-CSF	GM-CSF IL-3	GM-CSF IL-3 IL-5
Stages	Monoblast	Myelocyte
	Promonocyte	Promyelocyte
	Monocyte	Neutrophilic Myelocyte	Basophilic Myelocyte	Eosinophilic Myelocyte
		Neutrophilic Metamyelocyte	Basophilic Metamyelocyte	Eosinophilic Metamyelocyte
		Band Cell
		Neutrophil	Basophil	Eosinophil

Neutrophils

Under the stimulation of cytokines GM-CSF, G-CSF and IL-3 the CFU-GEMM differentiates into the CFU-GM, the common precursor for both neutrophils and monocytes. This then further differentiates into CFU-G.

Stages:

Myeloblast

Large cell with a large nucleus and which demonstrates basophilic staining. This stage exists for all granulocytes.

Promyelocyte

During this stage primary (azurophilic) granules are formed. This stage exists for all granulocytes.

Neutrophilic myelocyte

The developing neutrophil can now be differentiated from basophils and eosinophils as neutrophil specific granules are now being formed.

Neutrophilic metamyelocyte

At this stage mitosis can no longer occur. The nucleus elongates, becomes heterochromatic and has a kidney like shape. Differentiation is now much clearer from other granulocytes as the specific granules are in a far greater number than the primary granules formed in the promyelocyte stage.

Band cell

Nucleus elongates further and represents a horse shoe. Nucleus starts to segment.

Neutrophil

Mature neutrophil is formed and the nucleus is segmented and has 3 to 5 lobes. This lobular structure of the nucleus gives rise to the name polymorphonuclear neutrophil.

Basophils

Under the stimulation of GM-CSF and IL-3, the CFU-GEMM differentiates into CFU-Ba.

Stages:

Myeloblast & Promyelocyte

These stages are common to all granulocytes and no distinction can be made between different cell lines.

Basophilic myelocyte & metamyelocyte

Specific granules start to appear in the myelocyte stage, and as the cell develops into the metamyelocyte stage, mitosis ceases.

Basophil

Final nuclear shape is masked by the high density of cytoplasmic granules.

Eosinophils

Under the stimulation of GM-CSF, IL-3 and IL-5 the CFU-GEMM differentiates into the CFU-Eo.

Stages:

Myeloblast & Promyelocyte

These stages are common to all granulocytes and no distinction can be made between different cell lines.

Eosinophilic myelocyte & metamyelocyte

Specific granules start to appear in the myelocyte stage and once the cell has reached the metamyelocyte stage it cannot undergo further mitosis.

Eosinophil

Mature cell has a bilobed nucleus. There are species specific variations in granule size once stained.

Monocytes

Monocytes develop from the same precursor as neutrophils - the CFU-GM. This then differentiates into the CFU-M under the influence of GM-CSF, IL-3 and M-CSF.

Stages:

Monoblast

This is the first stage after cell has differentiated into the CFU-M.

Promonocyte

Cell has a large nucleus and basophilic cytoplasm and consists of two populations:- One rapidly dividing and the other slowly dividing, which acts as a reservoir.

Monocyte

Monocytes are incapable of mitosis and enter the circulation. They have a large kidney shaped nucleus with a slightly basophilic cytoplasm, which is often vacuolated.

Macrophage

Once the monocyte has entered tissue it differentiates into a macrophage.

Dendritic cells

These develop from the monoblast under the stimualtion of GM-CSF and IL-4 into an immature dendritic cell. This then develops into the mature dendritic cell under stimulation of TNF-α.

Lymphopoiesis

Lymphocytes develop from the CFU-L's. Those destined to become T cells leave the bone marrow and migrate to the thymus, and those destined to be B cells migrate to the spleen and gut-associated lymphoid tissue (GALT) or proliferate directly from the bone marrow.

	B cell	T cell
Differentiation	CFU-L
	▼Il-7 & Il-11	▼Il-7 & SCF
	B lymphoid cell progenitor	T lymphoid cell progenitor
	▼Il-3 & Il-7	▼Il-7	▼Il-2, IL-12 & Il-18	▼Il-3, Il-6, GM-CSF & SCF
	Pre-B cell	Pre-T cell	Pre-NK cell	Pre-Dendritic cell
Maturation site	Bone marrow, spleen or GALT Cloacal bursa (birds)	Thymus
Mature	B cell ▼(Antigen stim.) Plasma & Memory cell	T Cell Helper Cytotoxic Regulatory	NK cell	Dendritic cell

Note:

• Between the 'pre-[type] cell' stage and the final mature all the lymphocytes are referred to as 'immature [type] cells'.
• T cell differentiation into helper, cytotoxic and T cells with regulator functions is induced by Il-10 & TNF-γ