Neutrophils are the most numerous type of white blood cell and function as the immune system’s first responders to infection or injury. The creation of these cells is a process called differentiation, where a cell with broad potential develops a specific function. This transformation involves a series of complex and regulated steps.
The Origin of Neutrophils
All blood cells, including neutrophils, originate from the hematopoietic stem cell (HSC) found in bone marrow. HSCs can either create more stem cells or commit to a specific developmental path, a decision called lineage commitment. To become a neutrophil, an HSC commits to the myeloid lineage, becoming a common myeloid progenitor (CMP).
The pathway that produces granulocytes, including neutrophils, is known as granulopoiesis. This process involves the cell becoming a granulocyte-macrophage progenitor (GMP), which directs its transformation into a neutrophil.
The Stages of Maturation
The development from a progenitor into a mature neutrophil is a multi-stage process in the bone marrow that takes one to two weeks. This sequence is marked by changes in the cell’s size, nuclear shape, and cytoplasm contents. The process is divided into a mitotic phase, where cells can still divide, and a post-mitotic phase, where division stops and specialization accelerates.
Myeloblast
The myeloblast is the earliest identifiable cell committed to the neutrophil lineage. It is a large cell with a round nucleus containing fine, uncondensed genetic material called chromatin. Its cytoplasm is sparse and lacks the granules that define a mature neutrophil.
Promyelocyte
The next stage is the promyelocyte, notable for the appearance of primary (azurophilic) granules. These reddish-purple packets contain enzymes like myeloperoxidase and neutrophil elastase, which kill and digest microbes. The promyelocyte is the largest precursor in the neutrophil lineage and actively synthesizes these granules.
Myelocyte
The myelocyte is the final stage in which the cell can divide. During this stage, the cell produces secondary (specific) granules. These smaller granules contain substances like lactoferrin and collagenase for the inflammatory response. The nucleus begins to condense, and the cell starts to shrink.
Metamyelocyte
The metamyelocyte can no longer divide and enters the post-mitotic phase. The nucleus becomes indented, taking on a kidney-bean appearance. Its cytoplasm is filled with both primary and secondary granules.
Band Cell
Further condensation and elongation of the nucleus result in the band cell. The nucleus is constricted into a “C” or “S” shape but has not yet separated into lobes. Band cells are immature neutrophils and the final developmental stage in the bone marrow before release. A small number are found in the bloodstream, but their numbers increase during an infection as the body mobilizes reserves.
Segmented Neutrophil
The final stage is the segmented, or mature, neutrophil. The nucleus constricts into multiple lobes connected by thin filaments of chromatin. This feature allows the cell to deform and squeeze through narrow spaces to reach tissues. These cells are released from the bone marrow into circulation, ready to perform their immune functions.
Molecular Regulation of Differentiation
The progression through each stage of maturation is a regulated process governed by molecular signals. These signals act like instructions, telling cells when to divide, stop dividing, and which genes to activate. The main drivers of this process are proteins known as cytokines and growth factors.
Granulocyte Colony-Stimulating Factor (G-CSF) is a dominant regulator that promotes the survival and proliferation of neutrophil precursors, pushing them toward differentiation. It functions by binding to cell surface receptors, initiating internal signals that direct development.
These external signals are translated into action by transcription factors, which are proteins that bind to DNA and control gene expression. A prominent example is CCAAT/enhancer-binding protein alpha (C/EBPα), which activates genes for granulopoiesis while suppressing genes for other cell lineages.
Clinical Significance of Abnormal Differentiation
When the regulation of neutrophil differentiation is disrupted, it can lead to serious medical conditions. These disorders arise from either insufficient production of mature cells or uncontrolled proliferation of immature cells. One consequence is neutropenia, a condition with an abnormally low number of mature neutrophils in the blood, often due to impaired maturation in the bone marrow. Individuals with severe neutropenia are highly susceptible to bacterial and fungal infections because their bodies lack enough first responders.
Conversely, errors in differentiation can lead to leukemia. Acute Myeloid Leukemia (AML), for instance, is characterized by maturation arrest. In this disease, myeloid precursor cells acquire mutations that cause them to proliferate endlessly while failing to mature. This leads to an accumulation of dysfunctional blast cells in the bone marrow, which crowds out healthy blood cell production.