CFU-GEMM

CFU-GEMM
CFU-GEMM
	Red blood cells, white blood cells, and platelets are all derivatives of the CFU-GEMM cell.
Details
Gives rise to	Myeloid cells
Location	Bone marrow
Function	Colony forming unit
Identifiers
TH	H2.00.04.3.02008
	Anatomical terms of microanatomy [ edit on Wikidata]

Last updated July 05, 2024

CFU-GEMM is a colony forming unit that generates myeloid cells. CFU-GEMM cells are the oligopotential progenitor cells ^[1]^[2] for myeloid cells; they are thus also called common myeloid progenitor cells or myeloid stem cells. "GEMM" stands for granulocyte, erythrocyte, monocyte, megakaryocyte.^[3]

Structure

In current terminology, CFU-S refers to the pluripotent stem cells that can differentiate into all types of blood cells. CFU-S divides into two lineages: the lymphoid precursor (CFU-LSC) and the myeloid precursor (CFU-GEMM). The CFU-GEMM cell is capable of differentiating into white blood cells, red blood cells, and platelets, all of which are normally found in circulating blood.^[4]

It has been suggested that eosinophils do not derive from the common myeloid progenitor in humans.^[5]

In the adjacent image, CFU-GEMM is the scientific name for the "common myeloid progenitor" that is responsible for forming all the cells of the myeloid lineages. As observed in the image, CFU-GEMM is capable of producing a diverse set of cells. It matures into the megakaryocyte, erythrocyte, mast cell or myeloblast based on the presence of specific factors that encourage the cell to choose a lineage to follow.

Surface markers

The cells are characterized by expressing the cell surface markers CD33, CD34 and HLA-DR.^[6] These surface markers are proteins on the surface that are unique to specific cells and certain maturation periods, allowing researchers to differentiate between two different cells as well as what stage the cell is found in its developmental progression.

Development

Growth factors

The differentiation and proliferation of CFU-GEMM are promoted by growth factors, such as interleukins and cytokines. IL-3 and GM-CSF as single factors are equally active in stimulating CFU-GEMM, but the combination of both factors produces additive stimulatory effects upon CFU-GEMM. The growth of CFU-GEMM is stimulated by the stem cell factor, or SCF. SCF has been found also to synergize with GM-CSF, IL-6, IL-3, IL-11 or erythropoietin to increase the numbers of CFU-GEMM.^[6]

CFU-GEMM gives rise to CFU-GM (leading to monoblasts and myeloblasts), CFU-Meg (leading to megakaryoblasts), and CFU-E (leading to proerythroblasts). The stem cell will follow a specific lineage depending on the presence of certain growth factors and cytokines. The GM-CSF and IL-3 both work together to stimulate production of all lines. When erythropoietin (EPO) is present, red blood cell production from the CFU-GEMM will be activated. G-CSF, M-CSF, IL-5, IL-4, and IL-3 stimulate the production of neutrophils, monocytes, eosinophils, basophils, and platelets, respectively.^[4]

Research studies

Since the CFU-GEMM cell is a very early ancestor of the mature cells of the blood, it is not normally found in the blood. While present in bone marrow, the place where CFU-GEMM is most common is in the umbilical cord between a mother and baby. It has been discovered that these cells have a high replating efficiency, meaning that when taken from the umbilical cord and grown in culture, a high percentage of these cells are able to produce colonies. The results of studies conducted by Carow, Hangoc, and Broxmeyer in 1993 reveal that the CFU-GEMM can be classified as a stem cell due to its high replating efficiency in the presence of certain growth factors and cytokines.^[1]

The growth and production of CFU-GEMM and BFU-E depend on stimulatory factors from a source of burst-promoting activity (BPA) such as the release of interleukin-1 (IL-1) by monocytes, a has been studied in 1987. It has also been shown that fibroblasts are capable of secreting these BPAs, however only respond to regulatory molecule such as interleukin-1. The results showed that IL-1 increases the stimulatory effects of CFU-GEMM in a dose-dependent fashion with a maximum efficacy around 140 ng/mL. This study revealed that IL-1 plays an important role in the regulation of the production of stimulatory factors that influence the progenitor cells of hematopoiesis.^[7]

In another study in 2014, researchers were in search of molecules to stimulate the proliferation of long-term hematopoietic stem cells (LT-HSC). They tested a library of more than 5000 small molecules, with all except one (UM729) suppressing growth. A more potent analog was generated and named UM171. When compared to other similar chemicals, UM171 allowed for more HSC proliferation and lower apoptotic cell number compared to controls, along with a higher number in multipotential progenitors like CFU-GEMM. Furthermore, UM171 did not affect division rate. When used in conjunction with SR1, a known transcription factor, UM171 allowed for suppression of differentiation and led to increased CFU-GEMM growth. These results suggest that UM171+SR1 together enhance proliferation of progenitor cells and suppress differentiation.^[8]

Related Research Articles

A growth factor is a naturally occurring substance capable of stimulating cell proliferation, wound healing, and occasionally cellular differentiation. Usually it is a secreted protein or a steroid hormone. Growth factors are important for regulating a variety of cellular processes.

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.

Interleukins (ILs) are a group of cytokines that are expressed and secreted by white blood cells (leukocytes) as well as some other body cells. The human genome encodes more than 50 interleukins and related proteins.

Hematopoietic stem cells (HSCs) are the stem cells that give rise to other blood cells. This process is called haematopoiesis. In vertebrates, the 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.

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.

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: after removal of the signal peptide sequence, the mature protein contains 133 amino acids in its polypeptide chain. 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> Unipotent stem cell in the bone marrow

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.

Interleukin 5 (IL-5) is an interleukin produced by type-2 T helper cells and mast cells.

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.

Interleukin 7 (IL-7) is a protein that in humans is encoded by the IL7 gene.

Hemopoietic growth factors regulate the differentiation and proliferation of particular progenitor cells. Made available through recombinant DNA technology, they hold tremendous potential for medical uses when a person's natural ability to form blood cells is diminished or defective. Recombinant erythropoietin (EPO) is very effective in treating the diminished red blood cell production that accompanies end-stage kidney disease. Erythropoietin is a sialoglycoprotein hormone produced by peritubular cells of kidney.

The colony stimulating factor 1 (CSF1), also known as macrophage colony-stimulating factor (M-CSF), is a secreted cytokine which causes hematopoietic stem cells to differentiate into macrophages or other related cell types. Eukaryotic cells also produce M-CSF in order to combat intercellular viral infection. It is one of the three experimentally described colony-stimulating factors. M-CSF binds to the colony stimulating factor 1 receptor. It may also be involved in development of the placenta.

<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.

Granulopoiesis 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. Granulopoiesis takes place in the bone marrow. It leads to the production of three types of mature granulocytes: neutrophils, eosinophils and basophils.

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.

Colony stimulating factor 1 receptor (CSF1R), also known as macrophage colony-stimulating factor receptor (M-CSFR), and CD115, is a cell-surface protein encoded by the human CSF1R gene. CSF1R is a receptor that can be activated by two ligands: colony stimulating factor 1 (CSF-1) and interleukin-34 (IL-34). CSF1R is highly expressed in myeloid cells, and CSF1R signaling is necessary for the survival, proliferation, and differentiation of many myeloid cell types in vivo and in vitro. CSF1R signaling is involved in many diseases and is targeted in therapies for cancer, neurodegeneration, and inflammatory bone diseases.

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.

CFU-GM, also known as granulocyte–macrophage progenitor (GMP), is a colony forming unit. It is derived from CFU-GEMM. It is the precursor for monoblasts and myeloblasts. Production is stimulated by granulocyte macrophage colony-stimulating factor (GM-CSF).

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.

References

1 2 Carow CE, Hangoc G, Broxmeyer HE (February 1993). "Human multipotential progenitor cells (CFU-GEMM) have extensive replating capacity for secondary CFU-GEMM: an effect enhanced by cord blood plasma". Blood. 81 (4): 942–9. doi: 10.1182/blood.V81.4.942.942 . PMID 7679010.
↑ Roodman GD, LeMaistre CF, Clark GM, Page CP, Newcomb TF, Knight WA (August 1987). "CFU-GEMM correlate with neutrophil and platelet recovery in patients receiving autologous marrow transplantation after high-dose melphalan chemotherapy". Bone Marrow Transplant. 2 (2): 165–73. PMID 3332164.
↑ "Hem I WBC Morphology and Physiology". Archived from the original on December 25, 2008. Retrieved 2008-12-30.
1 2 Ciesla, Betty (2007). Hematology in Practice. Philadelphia, PA: F.A. Davis Company. ISBN 978-0-8036-1526-7.
↑ Mori Y, Iwasaki H, Kohno K, et al. (January 2009). "Identification of the human eosinophil lineage-committed progenitor: revision of phenotypic definition of the human common myeloid progenitor". J. Exp. Med. 206 (1): 183–93. doi:10.1084/jem.20081756. PMC 2626675 . PMID 19114669.
1 2 "CFU-GEMM (Cytokines & Cells Encyclopedia - COPE)". www.copewithcytokines.de. Retrieved 2015-11-19.
↑ Zucali, J.R.; Broxmeyer, H.E.; Dinarello, C.A.; Gross, M.A. & Weiner, R.S. (1987). "Regulation of Early Human Hematopoietic (CFU-GEMM and BFU-E) Progenitor Cells In Vitro by Interleukin 1-Induced Fibroblast-Conditioned Medium" (PDF). Blood. 69 (1): 33–37. doi: 10.1182/blood.V69.1.33.33 .
↑ Fares, I.; Chagaroui, J.; Gareau, Y. (December 6, 2014). "Pyrimido-Indole Derivatives Are Novel Agonists of Human Cord Blood Hematopoietic Stem Cell Self-Renewal". Blood. 124 (21): 650. doi:10.1182/blood.V124.21.650.650.

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[pmid7679010-1] 1 2 Carow CE, Hangoc G, Broxmeyer HE (February 1993). "Human multipotential progenitor cells (CFU-GEMM) have extensive replating capacity for secondary CFU-GEMM: an effect enhanced by cord blood plasma". Blood. 81 (4): 942–9. doi: 10.1182/blood.V81.4.942.942 . PMID 7679010.

[pmid3332164-2] Roodman GD, LeMaistre CF, Clark GM, Page CP, Newcomb TF, Knight WA (August 1987). "CFU-GEMM correlate with neutrophil and platelet recovery in patients receiving autologous marrow transplantation after high-dose melphalan chemotherapy". Bone Marrow Transplant. 2 (2): 165–73. PMID 3332164.

[urlHem_I_WBC_Morphology_and_Physiology-3] "Hem I WBC Morphology and Physiology". Archived from the original on December 25, 2008. Retrieved 2008-12-30.

[:1-4] 1 2 Ciesla, Betty (2007). Hematology in Practice. Philadelphia, PA: F.A. Davis Company. ISBN 978-0-8036-1526-7.

[pmid19114669-5] Mori Y, Iwasaki H, Kohno K, et al. (January 2009). "Identification of the human eosinophil lineage-committed progenitor: revision of phenotypic definition of the human common myeloid progenitor". J. Exp. Med. 206 (1): 183–93. doi:10.1084/jem.20081756. PMC 2626675 . PMID 19114669.

[:0-6] 1 2 "CFU-GEMM (Cytokines & Cells Encyclopedia - COPE)". www.copewithcytokines.de. Retrieved 2015-11-19.

[7] Zucali, J.R.; Broxmeyer, H.E.; Dinarello, C.A.; Gross, M.A. & Weiner, R.S. (1987). "Regulation of Early Human Hematopoietic (CFU-GEMM and BFU-E) Progenitor Cells In Vitro by Interleukin 1-Induced Fibroblast-Conditioned Medium" (PDF). Blood. 69 (1): 33–37. doi: 10.1182/blood.V69.1.33.33 .

[8] Fares, I.; Chagaroui, J.; Gareau, Y. (December 6, 2014). "Pyrimido-Indole Derivatives Are Novel Agonists of Human Cord Blood Hematopoietic Stem Cell Self-Renewal". Blood. 124 (21): 650. doi:10.1182/blood.V124.21.650.650.

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