Granulopoiesis

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Diagram of human haematopoiesis, showing all types of granulocyte precursors. Hematopoiesis (human) diagram en.svg
Diagram of human haematopoiesis, showing all types of granulocyte precursors.

Granulopoiesis (or granulocytopoiesis) is a part of haematopoiesis, that leads to the production of granulocytes. A granulocyte, also referred to as a polymorphonuclear leukocyte (PMN), is a type of white blood cell that has multi lobed nuclei, usually containing three lobes, and has a significant amount of cytoplasmic granules within the cell. [1] Granulopoiesis takes place in the bone marrow. [2] It leads to the production of three types of mature granulocytes: neutrophils (most abundant, making up to 60% of all white blood cells), eosinophils (up to 4%) and basophils (up to 1%). [3]

Contents

Stages of granulocyte development

Granulopoiesis is often divided into two parts;

1) Granulocyte lineage determination and

2) Committed granulopoiesis.

Granulocyte lineage determination

Granulopoiesis, as well as the rest of haematopoiesis, begins from a haematopoietic stem cells. These are multipotent 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. [4] They give rise to either a common lymphoid progenitor (CLP, a progenitor for all lymphoid cells) or a common myeloid progenitor, CMP, an oligopotent progenitor cell, that gives rise to the myeloid part of the haematopoietic tree. [1] The first stage of the myeloid lineage is a granulocyte - monocyte progenitor (GMP), still an oligopotent progenitor, which then develops into unipotent cells that will later on form a population of granulocytes, as well as a population of monocytes. The first unipotent cell in granulopoiesis is a myeloblast. [5]

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, 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. At this point, the nucleus is starting to shrink. At the stage of a metamyelocyte the cell nucleus is becoming kidney-shaped and it becomes even more bent in the stage of a band cell. The maturation is finished with the emergence of a segmented nucleus that is specific for a mature granulocyte. [1] [5] [6]

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 monocytes (high PU.1 levels) or to granulocytes (low PU.1 levels). [1] [7] 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, SMAD4 and HOX genes. [1] [8] [9]

Regulation by cytokines

Granulopoiesis is also regulated by cytokines to a certain extent. The main cytokines driving granulopoiesis are: GM-CSF (formation of GMPs from CMPs), G-CSF (commitment to the granulocyte lineage, formation of myeloblasts from GMPs), IL-3 (enhances the production of GM-CSF and G-CSF) and SCF. [10] [11] These are secreted by other haematopoietic cells in the bone marrow or at the site of inflammation as well as epithelial and endothelial cells. [2] [12]

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. [13] The master regulator of steady state granulopoiesis is C/EBPα. It restricts the cell cycle of immature cells by inhibition of CDK2 and CDK4 and promotes granulocytic differentiation. [14] Steady state production of granulocytes is activated after the engulfment of apoptotic granulocytes by tissue macrophages. [15]

Emergency granulopoiesis

Emergency granulopoiesis is a fundamental hematopoietic mechanism activated during acute infections or inflammatory conditions, leading to a swift increase in granulocyte production, especially neutrophils, in the bone marrow. This process is essential for enhancing the innate immune system's capability to confront pathogen invasions effectively. [16] [17] [18] Hematopoietic stem cells (HSCs) undergo significant transcriptional reprogramming in response to emergency conditions, transitioning from a lymphoid-biased state towards a myeloid-biased identity, thereby aligning the hematopoietic system's output with the urgent demand for granulocytes. [19]

Under normal conditions, steady-state granulopoiesis maintains granulocyte levels to meet physiological needs. However, after a major insult, typically a bacterial infection, the hematopoietic program switches from steady-state to emergency granulopoiesis. This switch is mediated by a transition from C/EBPα to C/EBPβ, the primary transcriptional regulator of emergency granulopoiesis. C/EBPβ enhances the production of granulocytes by promoting the progression of the cell cycle of myeloid progenitors at an accelerated rate, thereby generating a sufficient amount of new granulocytes to combat the insult. [20] [14]

The transcription factor CCAAT/enhancer binding protein β (C/EBPβ) is a critical regulator in this context, significantly influencing granulocyte lineage commitment and proliferation, especially noted during candidemia-induced scenarios [21] .

The genetic backdrop plays a crucial role in the dynamics of emergency granulopoiesis, as demonstrated by studies in TP53 haploinsufficient models, particularly in FANCC−/− mice, highlighting the intricate interplay between genetic predispositions and the granulopoietic response. [22] Additionally, recent advances have highlighted the importance of both direct and indirect pathogen sensing mechanisms. HSPCs are equipped with pathogen recognition receptors (PRRs) like Toll-like receptors (TLRs), enabling them to initiate myeloid differentiation and proliferation upon detecting pathogen-associated molecular patterns (PAMPs) [18] .

Neutrophils, as primary effector cells of the innate immune defense, originate from HSCs through a series of differentiation stages. The emergency granulopoiesis significantly accelerates this differentiation process, ensuring a rapid replenishment of neutrophil populations in response to systemic inflammatory stimuli, thus maintaining immune homeostasis [23] .

The clinical significance of understanding emergency granulopoiesis extends beyond basic science, influencing therapeutic strategies against infectious diseases and immune deficiencies. Balancing rapid neutrophil mobilization against the risk of immune dysregulation is critical, as imbalances can lead to severe conditions like acute respiratory distress syndrome and sepsis-induced organ dysfunctions. [23] [14]

Related Research Articles

<span class="mw-page-title-main">Haematopoiesis</span> Formation of blood cellular components

Haematopoiesis is the formation of blood cellular components. All cellular blood components are derived from haematopoietic stem cells. In a healthy adult human, roughly ten billion to a hundred billion new blood cells are produced per day, in order to maintain steady state levels in the peripheral circulation.

<span class="mw-page-title-main">Granulocyte colony-stimulating factor</span> Mammalian protein found in humans

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

<span class="mw-page-title-main">Hematopoietic stem cell</span> Stem cells that give rise to other blood cells

Hematopoietic stem cells (HSCs) are the stem cells that give rise to other blood cells. This process is called haematopoiesis. In vertebrates, the very first definitive HSCs arise from the ventral endothelial wall of the embryonic aorta within the (midgestational) aorta-gonad-mesonephros region, through a process known as endothelial-to-hematopoietic transition. In adults, haematopoiesis occurs in the red bone marrow, in the core of most bones. The red bone marrow is derived from the layer of the embryo called the mesoderm.

<span class="mw-page-title-main">Granulocyte-macrophage colony-stimulating factor</span> Mammalian protein found in Homo sapiens

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 functions as a cytokine. The pharmaceutical analogs of naturally occurring GM-CSF are called sargramostim and molgramostim.

<span class="mw-page-title-main">Interleukin 3</span> Protein-coding gene in the species Homo sapiens

Interleukin 3 (IL-3) is a protein that in humans is encoded by the IL3 gene localized on chromosome 5q31.1. Sometimes also called colony-stimulating factor, multi-CSF, mast cell growth factor, MULTI-CSF, MCGF; MGC79398, MGC79399: the protein contains 152 amino acids and its molecular weight is 17 kDa. IL-3 is produced as a monomer by activated T cells, monocytes/macrophages and stroma cells. The major function of IL-3 cytokine is to regulate the concentrations of various blood-cell types. It induces proliferation and differentiation in both early pluripotent stem cells and committed progenitors. It also has many more specific effects like the regeneration of platelets and potentially aids in early antibody isotype switching.

<span class="mw-page-title-main">Myeloblast</span>

The myeloblast is a unipotent stem cell which differentiates into the effectors of the granulocyte series. It is found in the bone marrow. Stimulation of myeloblasts by G-CSF and other cytokines triggers maturation, differentiation, proliferation and cell survival.

<span class="mw-page-title-main">CD34</span> Cluster of differentiation protocol that identifies cell surface antigens.

CD34 is a transmembrane phosphoglycoprotein protein encoded by the CD34 gene in humans, mice, rats and other species.

<span class="mw-page-title-main">Myeloid tissue</span> Tissue of bone marrow

Myeloid tissue, in the bone marrow sense of the word myeloid, is tissue of bone marrow, of bone marrow cell lineage, or resembling bone marrow, and myelogenous tissue is any tissue of, or arising from, bone marrow; in these senses the terms are usually used synonymously, as for example with chronic myeloid/myelogenous leukemia.

<span class="mw-page-title-main">Monoblast</span>

Monoblasts are the committed progenitor cells that differentiated from a committed macrophage or dendritic cell precursor (MDP) in the process of hematopoiesis. They are the first developmental stage in the monocyte series leading to a macrophage. Their myeloid cell fate is induced by the concentration of cytokines they are surrounded by during development. These cytokines induce the activation of transcription factors which push completion of the monoblast's myeloid cell fate. Monoblasts are normally found in bone marrow and do not appear in the normal peripheral blood. They mature into monocytes which, in turn, develop into macrophages. They then are seen as macrophages in the normal peripheral blood and many different tissues of the body. Macrophages can produce a variety of effector molecules that initiate local, systemic inflammatory responses. These monoblast differentiated cells are equipped to fight off foreign invaders using pattern recognition receptors to detect antigen as part of the innate immune response.

<span class="mw-page-title-main">G-CSF factor stem-loop destabilising element</span> RNA element

The G-CSF factor stem-loop destabilising element (SLDE) is an RNA element secreted by fibroblasts and endothelial cells in response to the inflammatory mediators interleukin-1 (IL-1) and tumour necrosis factor-alpha and by activated macrophages. The synthesis of G-CSF is regulated both transcriptionally and through control of mRNA stability. In unstimulated cells G-CSF mRNA is unstable but becomes stabilised in response to IL-1 or tumour necrosis factor alpha, and also in the case of monocytes and macrophages, in response to lipopolysaccharide. It is likely that the presence of the SLDE in the G-CSF mRNA contributes to the specificity of regulation of G-CSF mRNA and enhances the rate of shortening of the poly(A) tail.

<span class="mw-page-title-main">Granulocyte-macrophage colony-stimulating factor receptor</span> Protein-coding gene in humans

The granulocyte-macrophage colony-stimulating factor receptor, also known as CD116, is a receptor for granulocyte-macrophage colony-stimulating factor, which stimulates the production of white blood cells. In contrast to M-CSF and G-CSF which are lineage specific, GM-CSF and its receptor play a role in earlier stages of development. The receptor is primarily located on neutrophils, eosinophils and monocytes/macrophages, it is also on CD34+ progenitor cells (myeloblasts) and precursors for erythroid and megakaryocytic lineages, but only in the beginning of their development.

<span class="mw-page-title-main">FMS-like tyrosine kinase 3 ligand</span> Protein-coding gene in the species Homo sapiens

Fms-related tyrosine kinase 3 ligand (FLT3LG) is a protein which in humans is encoded by the FLT3LG gene.

Bone-marrow-derived macrophage (BMDM) refers to macrophage cells that are generated in a research laboratory from mammalian bone marrow cells. BMDMs can differentiate into mature macrophages in the presence of growth factors and other signaling molecules. Undifferentiated bone marrow cells are cultured in the presence of macrophage colony-stimulating factor. M-CSF is a cytokine and growth factor that is responsible for the proliferation and commitment of myeloid progenitors into monocytes. Macrophages have a wide variety of functions in the body including phagocytosis of foreign invaders and other cellular debris, releasing cytokines to trigger immune responses, and antigen presentation. BMDMs provide a large homogenous population of macrophages that play an increasingly important role in making macrophage-related research possible and financially feasible.

In hematology, myelopoiesis in the broadest sense of the term is the production of bone marrow and of all cells that arise from it, namely, all blood cells. In a narrower sense, myelopoiesis also refers specifically to the regulated formation of myeloid leukocytes (myelocytes), including eosinophilic granulocytes, basophilic granulocytes, neutrophilic granulocytes, and monocytes.

<span class="mw-page-title-main">CFU-GEMM</span>

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 granulocyte, erythrocyte, monocyte, megakaryocyte.

CFU-Meg is a colony forming unit. Haematopoiesis in the bone marrow starts off from a haematopoietic stem cell (HSC) and this can differentiate into the myeloid and lymphoid cell lineages. In order to eventually produce a megakaryocyte, the haematopoietic stem cell must generate myeloid cells, so it becomes a common myeloid progenitor, CFU-GEMM. This in turn develops into CFU-Meg, which is the colony forming unit that leads to the production of megakaryocytes.

Myeloid-derived suppressor cells (MDSC) are a heterogeneous group of immune cells from the myeloid lineage.

<span class="mw-page-title-main">Haematopoietic system</span>

The haematopoietic system is the system in the body involved in the creation of the cells of blood.

Many human blood cells, such as red blood cells (RBCs), immune cells, and even platelets all originate from the same progenitor cell, the hematopoietic stem cell (HSC). As these cells are short-lived, there needs to be a steady turnover of new blood cells and the maintenance of an HSC pool. This is broadly termed hematopoiesis. This event requires a special environment, termed the hematopoietic stem cell niche, which provides the protection and signals necessary to carry out the differentiation of cells from HSC progenitors. This niche relocates from the yolk sac to eventually rest in the bone marrow of mammals. Many pathological states can arise from disturbances in this niche environment, highlighting its importance in maintaining hematopoiesis.

Since haematopoietic stem cells cannot be isolated as a pure population, it is not possible to identify them under a microscope. Therefore, there are many techniques to isolate haematopoietic stem cells (HSCs). HSCs can be identified or isolated by the use of flow cytometry where the combination of several different cell surface markers is used to separate the rare HSCs from the surrounding blood cells. HSCs lack expression of mature blood cell markers and are thus, called Lin-. Lack of expression of lineage markers is used in combination with detection of several positive cell-surface markers to isolate HSCs. In addition, HSCs are characterized by their small size and low staining with vital dyes such as rhodamine 123 or Hoechst 33342.

References

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  17. ↑ Kondo, Motonari; Wagers, Amy J.; Manz, Markus G.; Prohaska, Susan S.; Scherer, David C.; Beilhack, Georg F.; Shizuru, Judith A.; Weissman, Irving L. (April 2003). "Biology of Hematopoietic Stem Cells and Progenitors: Implications for Clinical Application". Annual Review of Immunology. 21 (1): 759–806. doi:10.1146/annurev.immunol.21.120601.141007. ISSN   0732-0582. PMID   12615892.
  18. 1 2 Paudel, Sagar; Ghimire, Laxman; Jin, Liliang; Jeansonne, Duane; Jeyaseelan, Samithamby (2022-09-05). "Regulation of emergency granulopoiesis during infection". Frontiers in Immunology. 13. doi: 10.3389/fimmu.2022.961601 . ISSN   1664-3224. PMC   9485265 . PMID   36148240.
  19. ↑ Vanickova, Karolina; Milosevic, Mirko; Ribeiro Bas, Irina; Burocziova, Monika; Yokota, Asumi; Danek, Petr; Grusanovic, Srdjan; Chiliński, Mateusz; Plewczynski, Dariusz; Rohlena, Jakub; Hirai, Hideyo; Rohlenova, Katerina; Alberich-Jorda, Meritxell (December 2023). "Hematopoietic stem cells undergo a lymphoid to myeloid switch in early stages of emergency granulopoiesis". The EMBO Journal. 42 (23): e113527. doi:10.15252/embj.2023113527. ISSN   0261-4189. PMC   10690458 . PMID   37846891.
  20. ↑ Hasan, Shirin; Naqvi, Afsar R.; Rizvi, Asim (2018). "Transcriptional Regulation of Emergency Granulopoiesis in Leukemia". Frontiers in Immunology. 9: 481. doi: 10.3389/fimmu.2018.00481 . ISSN   1664-3224. PMC   5858521 . PMID   29593731.
  21. ↑ Satake, Sakiko; Hirai, Hideyo; Hayashi, Yoshihiro; Shime, Nobuaki; Tamura, Akihiro; Yao, Hisayuki; Yoshioka, Satoshi; Miura, Yasuo; Inaba, Tohru; Fujita, Naohisa; Ashihara, Eishi; Imanishi, Jiro; Sawa, Teiji; Maekawa, Taira (2012-11-01). "C/EBPβ Is Involved in the Amplification of Early Granulocyte Precursors during Candidemia-Induced "Emergency" Granulopoiesis". The Journal of Immunology. 189 (9): 4546–4555. doi:10.4049/jimmunol.1103007. ISSN   0022-1767. PMID   23024276.
  22. ↑ Hu, Liping; Huang, Weiqi; Bei, Ling; Broglie, Larisa; Eklund, Elizabeth A. (2018-03-15). "TP53 Haploinsufficiency Rescues Emergency Granulopoiesis in FANCC −/− Mice". The Journal of Immunology. 200 (6): 2129–2139. doi:10.4049/jimmunol.1700931. ISSN   0022-1767. PMC   5834788 . PMID   29427417.
  23. 1 2 Malengier-Devlies, Bert; Metzemaekers, Mieke; Wouters, Carine; Proost, Paul; Matthys, Patrick (2021-12-13). "Neutrophil Homeostasis and Emergency Granulopoiesis: The Example of Systemic Juvenile Idiopathic Arthritis". Frontiers in Immunology. 12. doi: 10.3389/fimmu.2021.766620 . ISSN   1664-3224. PMC   8710701 . PMID   34966386.
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