Granulopoiesis (or granulocytopoiesis) is a part of

haematopoiesis Haematopoiesis (, from Greek , 'blood' and 'to make'; also hematopoiesis in American English; sometimes also h(a)emopoiesis) is the formation of blood cellular components. All cellular blood components are derived from haematopoietic stem cells. ...

, that leads to the production of

granulocyte Granulocytes are cells in the innate immune system characterized by the presence of specific granules in their cytoplasm. Such granules distinguish them from the various agranulocytes. All myeloblastic granulocytes are polymorphonuclear. They ha ...

s. A

, also referred to as a polymorphonuclear leukocyte (PMN), is a type of

white blood cell White blood cells, also called leukocytes or leucocytes, are the cell (biology), cells of the immune system that are involved in protecting the body against both infectious disease and foreign invaders. All white blood cells are produced and de ...

that has multi lobed nuclei, usually containing three lobes, and has a significant amount of cytoplasmic granules within the cell. Granulopoiesis takes place in the

bone marrow Bone marrow is a semi-solid tissue found within the spongy (also known as cancellous) portions of bones. In birds and mammals, bone marrow is the primary site of new blood cell production (or haematopoiesis). It is composed of hematopoietic ce ...

. It leads to the production of three types of mature

granulocytes Granulocytes are cells in the innate immune system characterized by the presence of specific granules in their cytoplasm. Such granules distinguish them from the various agranulocytes. All myeloblastic granulocytes are polymorphonuclear. They hav ...

neutrophil Neutrophils (also known as neutrocytes or heterophils) are the most abundant type of granulocytes and make up 40% to 70% of all white blood cells in humans. They form an essential part of the innate immune system, with their functions varying in ...

s (most abundant, making up to 60% of all

s),

eosinophil Eosinophils, sometimes called eosinophiles or, less commonly, acidophils, are a variety of white blood cells (WBCs) and one of the immune system components responsible for combating multicellular parasites and certain infections in vertebrates. A ...

s (up to 4%) and

basophil Basophils are a type of white blood cell. Basophils are the least common type of granulocyte, representing about 0.5% to 1% of circulating white blood cells. However, they are the largest type of granulocyte. They are responsible for inflammator ...

s (up to 1%).

Stages of granulocyte development

Granulopoiesis is often divided into two parts; 1) Granulocyte lineage determination and 2) Commited granulopoiesis.

Granulocyte lineage determination

Granulopoiesis, as well as the rest of

, begins from a haematopoietic stem cells. These are

multipotent Pluripotency: These are the cells that can generate into any of the three Germ layers which imply Endodermal, Mesodermal, and Ectodermal cells except tissues like the placenta. According to Latin terms, Pluripotentia means the ability for many thin ...

cells that reside in the bone marrow niche and have the ability to give rise to all haematopoietic cells, as well as the ability of self renewal. They give rise to either a

common lymphoid progenitor Lymphopoiesis (lĭm'fō-poi-ē'sĭs) (or lymphocytopoiesis) is the generation of lymphocytes, which are one of the five types of white blood cells (WBCs). It is more formally known as lymphoid hematopoiesis. Disruption in lymphopoiesis can lead t ...

(CLP, a progenitor for all

lymphoid cells A lymphocyte is a type of white blood cell (leukocyte) in the immune system of most vertebrates. Lymphocytes include natural killer cells (which function in cell-mediated, cytotoxic innate immunity), T cells (for cell-mediated, cytotoxic adapt ...

) or a

common myeloid progenitor CFU-GEMM is a colony forming unit that generates myeloid cells. CFU-GEMM cells are the oligopotential progenitor cells for myeloid cells; they are thus also called common myeloid progenitor cells or myeloid stem cells. "GEMM" stands for granulocy ...

, CMP, an oligopotent progenitor cell, that gives rise to the myeloid part of the haematopoietic tree. The first stage of the myeloid lineage is a granulocyte - monocyte progenitor (GMP), still an oligopotent progenitor, which then develops into

unipotent In mathematics, a unipotent element ''r'' of a ring ''R'' is one such that ''r'' − 1 is a nilpotent element; in other words, (''r'' − 1)''n'' is zero for some ''n''. In particular, a square matrix ''M'' is a unipotent ...

cells that will later on form a population of

s, as well as a population of

monocytes Monocytes are a type of leukocyte or white blood cell. They are the largest type of leukocyte in blood and can differentiate into macrophages and conventional dendritic cells. As a part of the vertebrate innate immune system monocytes also infl ...

. The first unipotent cell in granulopoiesis is a myeloblast.

Committed granulopoiesis

Committed granulopoiesis consists of maturation stages of unipotent cells. The first cell that starts to resemble a granulocyte is a myeloblast. It is characterized by large oval nucleus that takes up most of the space in the cell and very little cytoplasm. The next developmental stage, a

promyelocyte A promyelocyte (or progranulocyte) is a granulocyte precursor, developing from the myeloblast and developing into the myelocyte. Promyelocytes measure 12-20 microns in diameter. The nucleus of a promyelocyte is approximately the same size as a m ...

, still has a large oval nucleus, but there is more cytoplasm in the cell at this point, also cytoplasmic granules are beginning to form. The development of granules continues with the next stage, a

myelocyte A myelocyte is a young cell of the granulocytic series, occurring normally in bone marrow (can be found in circulating blood when caused by certain diseases). Structure When stained with the usual dyes, the cytoplasm is distinctly basophilic ...

. At this point, the nucleus is starting to shrink. At the stage of a

metamyelocyte A metamyelocyte is a cell undergoing granulopoiesis, derived from a myelocyte, and leading to a band cell. It is characterized by the appearance of a bent nucleus, cytoplasmic granules, and the absence of visible nucleoli. (If the nucleus is n ...

the cell nucleus is becoming kidney-shaped and it becomes even more bent in the stage of a

band cell A band cell (also called band neutrophil, band form or stab cell) is a cell undergoing granulopoiesis, derived from a metamyelocyte, and leading to a mature granulocyte. It is characterized by having a curved but not lobular nucleus. The term ...

. The maturation is finished with the emergence of a segmented nucleus that is specific for a mature granulocyte.

Regulation of granulopoiesis

Transcriptional regulation

The maturation of granulocytic precursors is tightly regulated at transcriptional level. Granulocyte lineage determination is regulated by expression of C/EBPα, which is necessary for the transition from CMPs to GMPs and levels of PU.1, that drive the differentation from GMPs to

monocyte Monocytes are a type of leukocyte or white blood cell. They are the largest type of leukocyte in blood and can differentiate into macrophages and conventional dendritic cells. As a part of the vertebrate innate immune system monocytes also inf ...

s (high PU.1 levels) or to

s (low PU.1 levels). Committed granulopoiesis is regulated by C/EBPε and GFI-1, these two transcriptional factors are important for terminal granulocyte differentiation. Other transcriptional factors that regulate granulopoiesis are: CBF,

MYB MyB (Hangul: 마이비) was a South Korean girl group formed by Maroo Entertainment. The group debuted on August 25, 2015 with ''My Oh My'' and made a comeback on November 13, 2015 with ''Ddoddo'', before the group officially disbanded on December ...

SMAD4 SMAD4, also called SMAD family member 4, Mothers against decapentaplegic homolog 4, or DPC4 (Deleted in Pancreatic Cancer-4) is a highly conserved protein present in all metazoans. It belongs to the SMAD family of transcription factor proteins, ...

and

HOX gene Hox genes, a subset of homeobox genes, are a group of related genes that specify regions of the body plan of an embryo along the head-tail axis of animals. Hox proteins encode and specify the characteristics of 'position', ensuring that the cor ...

Regulation by cytokines

Granulopoiesis is also regulated by

cytokine Cytokines are a broad and loose category of small proteins (~5–25 kDa) important in cell signaling. Cytokines are peptides and cannot cross the lipid bilayer of cells to enter the cytoplasm. Cytokines have been shown to be involved in autocrin ...

s to a certain extent. The main cytokines driving granulopoiesis are:

GM-CSF Granulocyte-macrophage colony-stimulating factor (GM-CSF), also known as colony-stimulating factor 2 (CSF2), is a monomeric glycoprotein secreted by macrophages, T cells, mast cells, natural killer cells, endothelial cells and fibroblasts that ...

(formation of GMPs from CMPs),

G-CSF Granulocyte colony-stimulating factor (G-CSF or GCSF), also known as colony-stimulating factor 3 (CSF 3), is a glycoprotein that stimulates the bone marrow to produce granulocytes and stem cells and release them into the bloodstream. Functional ...

(commitment to the granulocyte lineage, formation of myeloblasts from GMPs), IL-3 (enhances the production of

and

) and SCF. These are secreted by other haematopoietic cells in the bone marrow or at the site of

inflammation Inflammation (from la, wikt:en:inflammatio#Latin, inflammatio) is part of the complex biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or Irritation, irritants, and is a protective response involving im ...

as well as

epithelial Epithelium or epithelial tissue is one of the four basic types of animal tissue, along with connective tissue, muscle tissue and nervous tissue. It is a thin, continuous, protective layer of compactly packed cells with a little intercellula ...

and

endothelial cells The endothelium is a single layer of squamous endothelial cells that line the interior surface of blood vessels and lymphatic vessels. The endothelium forms an interface between circulating blood or lymph in the lumen and the rest of the vessel ...

Types of granulopoiesis

Steady state granulopoiesis

Steady state granulopoiesis is a term used to describe the normal daily production of granulocytes. Granulocytes are short lived cells (their lifespan is between 6 and 8 hours) with a high cell turnover. The number of granulocytes produced every day is between 5 and 10 x 10¹⁰. The master regulator of steady state granulopoiesis is C/EBPα. It restricts the cell cycle of immature cells by inhibition of

CDK2 Cyclin-dependent kinase 2, also known as cell division protein kinase 2, or Cdk2, is an enzyme that in humans is encoded by the ''CDK2'' gene. The protein encoded by this gene is a member of the cyclin-dependent kinase family of Ser/Thr protein ...

and CDK4 and promotes granulocytic differentiation. Steady state production of granulocytes is activated after the engulfment of apoptotic granulocytes by tissue macrophages.

Emergency granulopoiesis

Steady state granulopoiesis is switched to a program termed emergency granulopoiesis after a major insult to the organism, usually a

bacterial infection Pathogenic bacteria are bacteria that can cause disease. This article focuses on the bacteria that are pathogenic to humans. Most species of bacteria are harmless and are often beneficial but others can cause infectious diseases. The number of ...

. The switch of the program is mediated by switch from C/EBPα to C/EBPβ, the main transcriptional regulator of emergency granulopoiesis. C/EBPβ enhances the production of granulocytes by promoting progression of the cell cycle of myeloid progenitors at accelerated rate, therefore generating sufficient amount of new granulocyte to fight the insult.

References

{{Blood physiology Hematopoiesis