Editing Haematopoiesis

{{Short description|Formation of blood cellular components}}
{{Use dmy dates|date=April 2020}}<!-- See Talk page section "Article date format" for more info. -->
[[File:Hematopoiesis simple.svg|thumb|400px|Diagram showing the development of different blood cells from haematopoietic stem cell to mature cells]]
'''Haematopoiesis''' ({{IPAc-en|h|ɪ|ˌ|m|æ|t|ə|p|ɔɪ|ˈ|iː|s|ɪ|s|,_|ˌ|h|iː|m|ə|t|oʊ|-|,_|ˌ|h|ɛ|m|ə|-}};<ref name=":0">{{cite Merriam-Webster|hematopoiesis |access-date=2022-05-16}}</ref><ref>{{cite Dictionary.com|haematopoiesis |access-date=2019-10-16}}</ref> {{etymology|grc|''{{wikt-lang|grc|αἷμα}}'' ({{grc-transl|αἷμα}})|blood||''{{wikt-lang|grc|ποιεῖν}}'' ({{grc-transl|ποιεῖν}})|to make}}; also '''hematopoiesis''' in [[American English]], sometimes '''h(a)emopoiesis''') is the formation of [[blood]] cellular components. All cellular blood components are derived from [[hematopoietic stem cell|haematopoietic stem cell]]s.<ref name="Birbrair n/a–n/a">{{Cite journal |last=Birbrair |first=Alexander |last2=Frenette |first2=Paul S. |date=2016-03-01 |title=Niche heterogeneity in the bone marrow |journal=Annals of the New York Academy of Sciences |language=en |volume=1370 |issue=1 |pages=82–96 |bibcode=2016NYASA1370...82B |doi=10.1111/nyas.13016 |issn=1749-6632 |pmc=4938003 |pmid=27015419}}</ref> In a healthy adult human, roughly ten billion ({{10^|10}}) to a hundred billion ({{10^|11}}) new blood cells are produced per day, in order to maintain steady state levels in the peripheral circulation.<ref name="T4">Semester 4 medical lectures at Uppsala University 2008 by Leif Jansson</ref><ref>{{Cite book |title=Medical Immunology |vauthors=Parslow TG, Stites DP, Terr AI, Imboden JB |publisher=Appleton & Lange |year=1997 |isbn=978-0-8385-6278-9 |edition=1}}</ref>{{Page needed|date=April 2020}}

== Process ==

=== Haematopoietic stem cells (HSCs) ===
{{Main|Hematopoietic stem cell}}
[[Hematopoietic stem cell|Haematopoietic stem cell]]s (HSCs) reside in the medulla of the bone ([[bone marrow]]) and have the unique ability to give rise to all of the different mature blood cell types and tissues.<ref name="Birbrair n/a–n/a"/> HSCs are self-renewing cells: when they differentiate, at least some of their daughter cells remain as HSCs so the pool of stem cells is not depleted.<ref name="Monga">{{Cite journal |vauthors=Monga I, Kaur K, Dhanda S |date=March 2022 |title=Revisiting hematopoiesis: applications of the bulk and single-cell transcriptomics dissecting transcriptional heterogeneity in hematopoietic stem cells |journal=Briefings in Functional Genomics |volume=21 |issue=3 |pages=159–176 |doi=10.1093/bfgp/elac002 |pmid=35265979}}</ref> This phenomenon is called [[Asymmetric cell division|asymmetric division.]]<ref>{{Cite journal |last=Morrison |first=J. |last2=Judith Kimble |year=2006 |title=Asymmetric and symmetric stem-cell divisions in development and cancer |url=https://deepblue.lib.umich.edu/bitstream/2027.42/62868/1/nature04956.pdf |journal=Nature |volume=441 |issue=7097 |pages=1068–74 |bibcode=2006Natur.441.1068M |doi=10.1038/nature04956 |pmid=16810241 |s2cid=715049 |hdl-access=free |hdl=2027.42/62868}}</ref> The other daughters of HSCs ([[myeloid]] and [[Lymphatic system|lymphoid]] progenitor cells) can follow any of the other differentiation pathways that lead to the production of one or more specific types of blood cell, but cannot renew themselves. The pool of progenitors is [[Homogeneity and heterogeneity|heterogeneous]] and can be divided into two groups; long-term self-renewing HSC and only transiently self-renewing HSC, also called short-terms.<ref>{{Cite journal |vauthors=Morrison SJ, Weissman IL |date=Nov 1994 |title=The long-term repopulating subset of hematopoietic stem cells is deterministic and isolable by phenotype. |journal=Immunity |volume=1 |issue=8 |pages=661–73 |doi=10.1016/1074-7613(94)90037-x |pmid=7541305}}</ref> This is one of the main vital processes in the body.{{cn|date=December 2024}}

=== Cell types ===
All blood cells are divided into three lineages.<ref>{{Cite web |title=Hematopoiesis from Pluripotent Stem Cells |url=http://www.ebioscience.com/resources/pathways/hematopoiesis-from-pluripotent-sem-cells.htm |access-date=25 April 2020 |website=Antibodies Resource Library |publisher=ThermoFisher Scientific}}</ref>
* [[Red blood cell]]s, which are also called erythrocytes, are the oxygen-carrying [[red blood cell|cell]]s. [[Red blood cells|Erythrocytes]] are functional, and are released into the blood. The number of reticulocytes, which are immature red blood cells, gives an estimate of the rate of [[erythropoiesis]].
* [[Lymphocyte]]s are the cornerstone of the adaptive immune system. They are derived from common lymphoid progenitors. The lymphoid lineage is composed of [[T-cell]]s, [[B-cell]]s, and [[natural killer cells]]. This is [[lymphopoiesis]].
* Cells of the myeloid lineage, which include [[granulocyte]]s, [[megakaryocyte]]s, monocytes, and [[macrophage]]s, are derived from common myeloid progenitors, and are involved in such diverse roles as [[innate immunity]] and [[blood clotting]]. This is [[myelopoiesis]].

[[Granulopoiesis]] (or granulocytopoiesis) is haematopoiesis of granulocytes, except [[mast cell]]s which are granulocytes but with an extramedullar maturation.<ref>{{Cite book |last=Mahler |title=Haschek and Rousseaux's handbook of toxicologic pathology |date=2013 |publisher=Academic Press |others=associate editors, Brad Bolon and Ricardo Ochoa; illustrations editor, Beth W. |isbn=978-0-12-415759-0 |editor-last=Haschek |editor-first=Wanda |edition=Third |location=[S.l.] |page=1863 |editor-last2=Rousseaux |editor-first2=Colin G. |editor-last3=Wallig |editor-first3=Matthew A.}}</ref>

[[Thrombopoiesis]] is haematopoiesis of [[Platelet|thrombocytes (platelets)]].

===Terminology===
Between 1948 and 1950, the Committee for Clarification of the Nomenclature of Cells and Diseases of the Blood and Blood-forming Organs issued reports on the nomenclature of blood cells.<ref>{{Cite journal |date=May 1948 |title=FIRST report of the committee for clarification of the nomenclature of cells and diseases of the blood and blood-forming organs |url=https://academic.oup.com/ajcp/article-abstract/18/5_ts/443/4828542 |journal=American Journal of Clinical Pathology |volume=18 |issue=5 |pages=443–50 |doi=10.1093/ajcp/18.5_ts.443 |pmid=18913573 |url-access=limited}}</ref><ref>{{Cite journal |date=June 1950 |title=THIRD, fourth and fifth reports of the committee for clarification of the nomenclature of cells and diseases of the blood and blood-forming organs |url=https://academic.oup.com/ajcp/article-abstract/20/6/562/1767294 |journal=American Journal of Clinical Pathology |volume=20 |issue=6 |pages=562–79 |doi=10.1093/ajcp/20.6.562 |pmid=15432355 |url-access=limited}}</ref> An overview of the terminology is shown below, from earliest to final stage of development:{{cn|date=September 2024}}
* [root]blast
* pro[root]cyte
* [root]cyte
* meta[root]cyte
* mature cell name

The root for erythrocyte colony-forming units (CFU-E) is "rubri", for granulocyte-monocyte colony-forming units (CFU-GM) is "granulo" or "myelo" and "mono", for lymphocyte colony-forming units (CFU-L) is "lympho" and for megakaryocyte colony-forming units (CFU-Meg) is "megakaryo". According to this terminology, the stages of red blood cell formation would be: rubriblast, prorubricyte, rubricyte, metarubricyte, and erythrocyte. However, the following nomenclature seems to be, at present, the most prevalent:

{| class="wikitable"
! Committee || "lympho" || "rubri" || "granulo" or "myelo" || "mono" || "megakaryo"
|-
|''Lineage''||[[Lymphoid]]||[[Myeloid]]|| Myeloid || Myeloid || Myeloid
|-
|''CFU''||[[CFU-L]]||[[CFU-GEMM]]→[[CFU-E]]|| CFU-GEMM→[[CFU-GM]]→[[CFU-G]]|| CFU-GEMM→[[CFU-GM]]→[[CFU-M]]|| CFU-GEMM→[[CFU-Meg]]
|-
|''Process''||[[lymphocytopoiesis]]||[[erythropoiesis]]||[[granulocytopoiesis]]||[[monocytopoiesis]]||[[thrombocytopoiesis]]
|-
|''[root]blast''||[[Lymphoblast]]||[[Proerythroblast]]||[[Myeloblast]]||[[Monoblast]]||[[Megakaryoblast]]
|-
|''pro[root]cyte''||[[Prolymphocyte]]||[[Polychromatophilic erythrocyte]]||[[Promyelocyte]]||[[Promonocyte]]||[[Promegakaryocyte]]
|-
|''[root]cyte''|| – ||[[Normoblast]]||[[Eosinophilic myelocyte|Eosino]]/[[neutrophilic myelocyte|neutro]]/[[basophilic myelocyte]]||  ||[[Megakaryocyte]]
|-
|''meta[root]cyte''|| Large [[lymphocyte]]||[[Reticulocyte]]|| Eosinophilic/neutrophilic/basophilic [[metamyelocyte]], Eosinophilic/neutrophilic/basophilic [[band cell]]||[[Early monocyte]]|| -
|-
|''mature cell name''|| Small [[lymphocyte]]||[[Erythrocyte]]||[[granulocytes]] ([[Eosinophil|Eosino]]/[[neutrophil|neutro]]/[[basophil]]) ||[[Monocyte]]||[[thrombocytes]] ([[Platelets]])
|}

[[Osteoclast]]s also arise from hemopoietic cells of the monocyte/neutrophil lineage, specifically CFU-GM.

==Location==
{{main|Haematopoietic system}}
[[Image:Hematopoesis EN.svg|thumb|350px|Sites of haematopoiesis (human) in pre- and postnatal periods]]
In developing embryos, blood formation occurs in aggregates of blood cells in the yolk sac, called [[blood islands]]. As development progresses, blood formation occurs in the [[spleen]], [[liver]] and [[lymph nodes]].<ref name="Embrio_Hematopoiesis">{{Cite journal |last=Singh |first=Ranbir |last2=Soman-Faulkner |first2=Kristina |last3=Sugumar |first3=Kavin |year=2022 |title=Embryology, Hematopoiesis |url=https://www.ncbi.nlm.nih.gov/books/NBK544245/ |publisher=StatPearls |pmid=31334965 |access-date=4 September 2022 |website=NCBI}}</ref> When [[bone marrow]] develops, it eventually assumes the task of forming most of the blood cells for the entire organism.<ref name="Birbrair n/a–n/a"/> However, maturation, activation, and some proliferation of lymphoid cells occurs in the spleen, [[thymus]], and lymph nodes. In children, haematopoiesis occurs in the marrow of the long bones such as the femur and tibia. In adults, it occurs mainly in the pelvis, cranium, vertebrae, and sternum.<ref>{{Cite journal |vauthors=Fernández KS, de Alarcón PA |date=Dec 2013 |title=Development of the hematopoietic system and disorders of hematopoiesis that present during infancy and early childhood. |url=https://www.sciencedirect.com/science/article/abs/pii/S0031395513001132 |journal=Pediatric Clinics of North America |volume=60 |issue=6 |pages=1273–89 |doi=10.1016/j.pcl.2013.08.002 |pmid=24237971 |url-access=limited}}</ref>

===Extramedullary===
In some cases, the liver, thymus, and spleen may resume their haematopoietic function, if necessary. This is called ''[[extramedullary hematopoiesis|extramedullary haematopoiesis]]''. It may cause these organs to increase in size substantially. During fetal development, since bones and thus the bone marrow develop later, the liver functions as the main haematopoietic organ. Therefore, the liver is enlarged during development.<ref>{{Cite journal |vauthors=Georgiades CS, Neyman EG, Francis IR, Sneider MB, Fishman EK |date=Nov 2002 |title=Typical and atypical presentations of extramedullary hemopoiesis. |journal=AJR. American Journal of Roentgenology |volume=179 |issue=5 |pages=1239–43 |doi=10.2214/ajr.179.5.1791239 |pmid=12388506 |doi-access=free}}</ref> Extramedullary haematopoiesis and myelopoiesis may supply [[leukocytes]] in [[cardiovascular disease]] and inflammation during adulthood.<ref>{{Cite journal |last=Swirski |first=Filip K. |last2=Libby |first2=Peter |last3=Aikawa |first3=Elena |last4=Alcaide |first4=Pilar |last5=Luscinskas |first5=F. William |last6=Weissleder |first6=Ralph |last7=Pittet |first7=Mikael J. |date=2 January 2007 |title=Ly-6Chi monocytes dominate hypercholesterolemia-associated monocytosis and give rise to macrophages in atheromata |journal=Journal of Clinical Investigation |volume=117 |issue=1 |pages=195–205 |doi=10.1172/JCI29950 |pmc=1716211 |pmid=17200719 |doi-access=free}}</ref><ref>{{Cite journal |vauthors=Swirski FK, Nahrendorf M, Etzrodt M, Wildgruber M, Cortez-Retamozo V, Panizzi P, Figueiredo JL, Kohler RH, Chudnovskiy A, Waterman P, Aikawa E, Mempel TR, Libby P, Weissleder R, Pittet MJ |date=30 July 2009 |title=Identification of Splenic Reservoir Monocytes and Their Deployment to Inflammatory Sites |journal=Science |volume=325 |issue=5940 |pages=612–616 |bibcode=2009Sci...325..612S |doi=10.1126/science.1175202 |pmc=2803111 |pmid=19644120}}</ref> Splenic [[macrophages]] and [[adhesion molecules]] may be involved in regulation of extramedullary myeloid cell generation in [[cardiovascular disease]].<ref>{{Cite journal |last=Dutta |first=P |last2=Hoyer |first2=FF |last3=Grigoryeva |first3=LS |last4=Sager |first4=HB |last5=Leuschner |first5=F |last6=Courties |first6=G |last7=Borodovsky |first7=A |last8=Novobrantseva |first8=T |last9=Ruda |first9=VM |last10=Fitzgerald |first10=K |last11=Iwamoto |first11=Y |last12=Wojtkiewicz |first12=G |last13=Sun |first13=Y |last14=Da Silva |first14=N |last15=Libby |first15=P |date=6 April 2015 |title=Macrophages retain hematopoietic stem cells in the spleen via VCAM-1. |journal=The Journal of Experimental Medicine |volume=212 |issue=4 |pages=497–512 |doi=10.1084/jem.20141642 |pmc=4387283 |pmid=25800955 |doi-access=free |first17=FK |last18=Weissleder |first18=R |last19=Nahrendorf |first19=M |last17=Swirski |first16=DG |last16=Anderson}}</ref><ref>{{Cite journal |last=Dutta |first=P |last2=Hoyer |first2=FF |last3=Sun |first3=Y |last4=Iwamoto |first4=Y |last5=Tricot |first5=B |last6=Weissleder |first6=R |last7=Magnani |first7=JL |last8=Swirski |first8=FK |last9=Nahrendorf |first9=M |date=September 2016 |title=E-Selectin Inhibition Mitigates Splenic HSC Activation and Myelopoiesis in Hypercholesterolemic Mice With Myocardial Infarction. |journal=Arteriosclerosis, Thrombosis, and Vascular Biology |volume=36 |issue=9 |pages=1802–8 |doi=10.1161/ATVBAHA.116.307519 |pmc=5001901 |pmid=27470513 |doi-access=free}}</ref>

==Maturation==
[[File:Hematopoiesis (human) diagram en.svg|thumb|400px|More detailed and comprehensive diagram that shows the development of different blood cells in humans:{{unordered list
| The morphological characteristics of the hematopoietic cells are shown as seen in a Wright's stain, May-Giemsa stain or May-Grünwald-Giemsa stain. Alternative names of certain cells are indicated between parentheses.
| Certain cells may have more than one characteristic appearance. In these cases, more than one representation of the same cell has been included.
| Together, the monocyte and the lymphocytes comprise the agranulocytes, as opposed to the granulocytes (basophil, neutrophil and eosinophil) that are produced during granulopoiesis.
| B., N. and E. stand for Basophilic, Neutrophilic and Eosinophilic, respectively – as in Basophilic promyelocyte. For  lymphocytes, the T and B are actual designations.}}{{ordered list
| The polychromatic erythrocyte (reticulocyte) at the right shows its characteristic appearance when stained with methylene blue or Azure B.
| The erythrocyte at the right is a more accurate representation of its appearance in reality when viewed through a microscope.
| Other cells that arise from the monocyte: osteoclast, microglia (central nervous system), Langerhans cell (epidermis), Kupffer cell (liver).
| For clarity, the T and B lymphocyte are split to better indicate that the plasma cell arises from the B-cell. Note that there is no difference in the appearance of B- and T-cells unless specific staining is applied.}}
]]
As a stem cell matures it undergoes changes in [[gene expression]] that limit the cell types that it can become and moves it closer to a specific cell type ([[cellular differentiation]]). These changes can often be tracked by monitoring the presence of proteins on the surface of the cell. Each successive change moves the cell closer to the final cell type and further limits its potential to become a different cell type.{{citation needed|date=December 2021}}

=== Cell fate determination ===
Two models for haematopoiesis have been proposed: determinism and stochastic theory.<ref>{{Cite book |last=Kimmel |first=Marek |title=A Systems Biology Approach to Blood |date=2014-01-01 |isbn=978-1-4939-2094-5 |series=Advances in Experimental Medicine and Biology |volume=844 |pages=119–152 |chapter=Stochasticity and Determinism in Models of Hematopoiesis |doi=10.1007/978-1-4939-2095-2_7 |issn=0065-2598 |pmid=25480640}}</ref> For the stem cells and other undifferentiated blood cells in the bone marrow, the determination is generally explained by the ''determinism'' theory of haematopoiesis, saying that colony stimulating factors and other factors of the haematopoietic microenvironment determine the cells to follow a certain path of cell differentiation.<ref name="Birbrair n/a–n/a"/> This is the classical way of describing haematopoiesis. In ''stochastic'' ''theory,'' undifferentiated blood cells differentiate to specific cell types by randomness. This theory has been supported by experiments showing that within a population of mouse haematopoietic progenitor cells, underlying stochastic variability in the distribution of [[Sca-1]], a [[stem cell]] factor, subdivides the population into groups exhibiting variable rates of [[cellular differentiation]]. For example, under the influence of [[erythropoietin]] (an erythrocyte-differentiation factor), a subpopulation of cells (as defined by the levels of Sca-1) differentiated into [[Red blood cell|erythrocytes]] at a sevenfold higher rate than the rest of the population.<ref>{{Cite journal |last=Chang |first=Hannah H. |last2=Hemberg |first2=Martin |last3=Barahona |first3=Mauricio |last4=Ingber |first4=Donald E. |last5=Huang |first5=Sui |year=2008 |title=Transcriptome-wide noise controls lineage choice in mammalian progenitor cells |journal=Nature |volume=453 |issue=7194 |pages=544–547 |bibcode=2008Natur.453..544C |doi=10.1038/nature06965 |pmc=5546414 |pmid=18497826}}</ref> Furthermore, it was shown that if allowed to grow, this subpopulation re-established the original subpopulation of cells, supporting the theory that this is a stochastic, reversible process. Another level at which stochasticity may be important is in the process of apoptosis and self-renewal. In this case, the haematopoietic microenvironment prevails upon some of the cells to survive and some, on the other hand, to perform [[apoptosis]] and die.<ref name="Birbrair n/a–n/a"/> By regulating this balance between different cell types, the bone marrow can alter the quantity of different cells to ultimately be produced.<ref>{{Cite journal |last=Alenzi |first=FQ |last2=Alenazi, BQ |last3=Ahmad, SY |last4=Salem, ML |last5=Al-Jabri, AA |last6=Wyse, RK |date=Mar 2009 |title=The haemopoietic stem cell: between apoptosis and self renewal. |journal=The Yale Journal of Biology and Medicine |volume=82 |issue=1 |pages=7–18 |pmc=2660591 |pmid=19325941}}</ref>

=== Growth factors ===
[[File:Hematopoietic growth factors.png|thumb|350px|Diagram including some of the important cytokines that determine which type of blood cell will be created.<ref name=lodish/> SCF= [[Stem cell factor]]; Tpo= [[Thrombopoietin]]; IL= [[Interleukin]]; GM-CSF= [[Granulocyte Macrophage-colony stimulating factor]]; Epo= [[Erythropoietin]]; M-CSF= [[Macrophage-colony stimulating factor]]; G-CSF= [[Granulocyte-colony stimulating factor]]; SDF-1= [[Stromal cell-derived factor-1]]; FLT-3 ligand= FMS-like tyrosine kinase 3 ligand; TNF-a = [[Tumor necrosis factor-alpha|Tumour necrosis factor-alpha]]; TGFβ = [[Transforming growth factor]] beta<ref name=lodish/><ref>{{Cite book |last=Rod Flower |title=Rang & Dale's pharmacology |last2=Humphrey P. Rang |last3=Maureen M. Dale |last4=Ritter, James M. |publisher=Churchill Livingstone |year=2007 |isbn=978-0-443-06911-6 |location=Edinburgh}}</ref>|alt=]]
Red and white blood cell production is regulated with great precision in healthy humans, and the production of leukocytes is rapidly increased during infection. The proliferation and self-renewal of these cells depend on growth factors. One of the key players in self-renewal and development of haematopoietic cells is [[stem cell factor]] (SCF),<ref>{{Cite journal |last=Broudy |first=VC |date=Aug 15, 1997 |title=Stem cell factor and hematopoiesis. |journal=Blood |volume=90 |issue=4 |pages=1345–64 |doi=10.1182/blood.V90.4.1345 |pmid=9269751 |doi-access=free}}</ref> which binds to the c-kit receptor on the HSC. Absence of SCF is lethal. There are other important [[glycoprotein]] growth factors which regulate the proliferation and maturation, such as [[interleukin]]s [[Interleukin 2|IL-2]], [[Interleukin 3|IL-3]], [[Interleukin 6|IL-6]], [[Interleukin 7|IL-7]]. Other factors, termed [[colony-stimulating factors]] (CSFs), specifically stimulate the production of committed cells. Three CSFs are [[granulocyte-macrophage CSF]] (GM-CSF), [[granulocyte CSF]] (G-CSF) and [[macrophage CSF]] (M-CSF).<ref>{{Cite journal |last=Ketley |first=N. J. |last2=A. C. Newland |year=1997 |title=Haemopoietic growth factors. |journal=Postgrad Med J |volume=73 |issue=858 |pages=215–221 |doi=10.1136/pgmj.73.858.215 |pmc=2431295 |pmid=9156123}}</ref> These stimulate [[granulocyte]] formation and are active on either [[progenitor cells]] or end product cells.{{cn|date=September 2024}}

[[Erythropoietin]] is required for a myeloid progenitor cell to become an erythrocyte.<ref name="lodish">Molecular cell biology. Lodish, Harvey F. 5. ed. : – New York : W. H. Freeman and Co., 2003, 973 s. b ill. {{ISBN|0-7167-4366-3}}
----{{Cite book |url=https://www.ncbi.nlm.nih.gov/books/NBK21590/figure/A7080/ |title=Molecular Cell Biology |vauthors=Lodish H, Berk A, Zipursky SL, Matsudaira P, Baltimore D, Darnell J |publisher=W. H. Freeman |year=2000 |isbn=0-7167-3136-3 |edition=4th |location=New York |at=Figure 24-8: Formation of differentiated blood cells from hematopoietic stem cells in the bone marrow |chapter=Cancers Originate in Proliferating Cells |via=NCBI Bookshelf}}</ref> On the other hand, [[thrombopoietin]] makes myeloid progenitor cells differentiate to [[megakaryocyte]]s ([[thrombocyte]]-forming cells).<ref name=lodish/> The diagram to the right provides examples of cytokines and the differentiated blood cells they give rise to.<ref>{{Cite journal |last=Hauke |first=Ralph |last2=Stefano R. Tarantolo |date=November 2000 |title=Hematopoietic Growth Factors |journal=Laboratory Medicine |volume=31 |issue=11 |pages=613–5 |doi=10.1309/HNTM-ELUV-AV9G-MA1P |doi-access=free}}</ref>

===Transcription factors===
Growth factors initiate [[signal transduction]] pathways, which lead to activation of [[transcription factors]]. Growth factors elicit different outcomes depending on the combination of factors and the cell's stage of differentiation. For example, long-term expression of [[PU.1]] results in myeloid commitment, and short-term induction of PU.1 activity leads to the formation of immature eosinophils.<ref>{{Cite journal |last=Engel |first=I |last2=Murre, C |date=Oct 1999 |title=Transcription factors in hematopoiesis. |url=https://www.sciencedirect.com/science/article/pii/S0959437X99000088 |journal=Current Opinion in Genetics & Development |volume=9 |issue=5 |pages=575–9 |doi=10.1016/s0959-437x(99)00008-8 |pmid=10508690 |url-access=subscription}}</ref> Recently, it was reported that transcription factors such as [[NF-κB]] can be regulated by [[microRNA]]s (e.g., miR-125b) in haematopoiesis.<ref>{{Cite journal |last=O'Connell |first=R |last2=Rao, D. |last3=Baltimore, D |year=2012 |title=microRNA Regulation of Inflammatory Responses |journal=Annual Review of Immunology |volume=30 |pages=295–312 |doi=10.1146/annurev-immunol-020711-075013 |pmid=22224773 |doi-access=free}}</ref>

The first key player of differentiation from HSC to a multipotent progenitor (MPP) is transcription factor CCAAT-enhancer binding protein α ([[C/EBP]]α). Mutations in C/EBPα are associated with [[acute myeloid leukaemia]].<ref>{{Cite journal |last=Ho |first=PA |last2=Alonzo, TA |last3=Gerbing, RB |last4=Pollard, J |last5=Stirewalt, DL |last6=Hurwitz, C |last7=Heerema, NA |last8=Hirsch, B |last9=Raimondi, SC |last10=Lange, B |last11=Franklin, JL |last12=Radich, JP |last13=Meshinchi, S |date=Jun 25, 2009 |title=Prevalence and prognostic implications of CEBPA mutations in pediatric acute myeloid leukemia (AML): a report from the Children's Oncology Group. |journal=Blood |volume=113 |issue=26 |pages=6558–66 |doi=10.1182/blood-2008-10-184747 |pmc=2943755 |pmid=19304957}}</ref> From this point, cells can either differentiate along the Erythroid-megakaryocyte lineage or lymphoid and myeloid lineage, which have common progenitor, called lymphoid-primed multipotent progenitor. There are two main transcription factors. PU.1 for Erythroid-megakaryocyte lineage and [[GATA-1]], which leads to a lymphoid-primed multipotent progenitor.<ref>{{Cite journal |last=Woolthuis |first=Carolien M. |last2=Park |first2=Christopher Y. |date=2016-03-10 |title=Hematopoietic stem/progenitor cell commitment to the megakaryocyte lineage |journal=Blood |volume=127 |issue=10 |pages=1242–1248 |doi=10.1182/blood-2015-07-607945 |issn=0006-4971 |pmc=5003506 |pmid=26787736 |s2cid=206939258 |doi-access=free}}</ref>

Other transcription factors include Ikaros<ref>{{Cite journal |last=Thompson |first=Elizabeth C. |last2=Cobb |first2=Bradley S. |last3=Sabbattini |first3=Pierangela |last4=Meixlsperger |first4=Sonja |last5=Parelho |first5=Vania |last6=Liberg |first6=David |last7=Taylor |first7=Benjamin |last8=Dillon |first8=Niall |last9=Georgopoulos |first9=Katia |date=2007-03-01 |title=Ikaros DNA-binding proteins as integral components of B cell developmental-stage-specific regulatory circuits |journal=Immunity |volume=26 |issue=3 |pages=335–344 |doi=10.1016/j.immuni.2007.02.010 |issn=1074-7613 |pmid=17363301 |doi-access=free}}</ref> ([[B cell]] development), and [[GFI1|Gfi1]]<ref>{{Cite journal |last=Suzuki |first=Junpei |last2=Maruyama |first2=Saho |last3=Tamauchi |first3=Hidekazu |last4=Kuwahara |first4=Makoto |last5=Horiuchi |first5=Mika |last6=Mizuki |first6=Masumi |last7=Ochi |first7=Mizuki |last8=Sawasaki |first8=Tatsuya |last9=Zhu |first9=Jinfang |date=2016-04-01 |title=Gfi1, a transcriptional repressor, inhibits the induction of the T helper type 1 programme in activated CD4 T cells |journal=Immunology |volume=147 |issue=4 |pages=476–487 |doi=10.1111/imm.12580 |issn=1365-2567 |pmc=4799889 |pmid=26749286}}</ref> (promotes [[T helper cell|Th2]] development and inhibits Th1) or [[IRF8]]<ref>{{Cite journal |last=Sasaki |first=Haruka |last2=Kurotaki |first2=Daisuke |last3=Tamura |first3=Tomohiko |date=2016-04-01 |title=Regulation of basophil and mast cell development by transcription factors |journal=Allergology International |volume=65 |issue=2 |pages=127–134 |doi=10.1016/j.alit.2016.01.006 |issn=1440-1592 |pmid=26972050 |doi-access=free}}</ref> ([[Basophil granulocyte|basophils]] and [[mast cell]]s). Significantly, certain factors elicit different responses at different stages in the haematopoiesis. For example, CEBPα in neutrophil development or [[SPI1|PU.1]] in monocytes and dendritic cell development. It is important to note that processes are not unidirectional: differentiated cells may regain attributes of progenitor cells.<ref name=":0" />

An example is [[PAX5]] factor, which is important in B cell development and associated with lymphomas.<ref>{{Cite journal |last=O'Brien |first=P |last2=Morin |first2=P Jr |last3=Ouellette |first3=RJ |last4=Robichaud |first4=GA |date=Dec 15, 2011 |title=The Pax-5 gene: a pluripotent regulator of B-cell differentiation and cancer disease |journal=Cancer Research |volume=71 |issue=24 |pages=7345–50 |doi=10.1158/0008-5472.CAN-11-1874 |pmid=22127921 |doi-access=free}}</ref> Surprisingly, pax5 conditional knock out mice allowed peripheral mature B cells to de-differentiate to early bone marrow progenitors. These findings show that transcription factors act as caretakers of differentiation level and not only as initiators.<ref>{{Cite journal |last=Cobaleda |first=C |last2=Jochum, W |last3=Busslinger, M |date=Sep 27, 2007 |title=Conversion of mature B cells into T cells by dedifferentiation to uncommitted progenitors |url=https://www.nature.com/articles/nature06159 |journal=Nature |volume=449 |issue=7161 |pages=473–7 |bibcode=2007Natur.449..473C |doi=10.1038/nature06159 |pmid=17851532 |s2cid=4414856 |url-access=subscription}}</ref>

[[Mutations]] in transcription factors are tightly connected to blood cancers, as [[acute myeloid leukaemia|acute myeloid leukemia]] (AML) or [[acute lymphoblastic leukemia]] (ALL). For example, Ikaros is known to be regulator of numerous biological events. Mice with no Ikaros lack [[B cell]]s, [[Natural killer]] and [[T cell]]s.<ref>{{Cite journal |last=Wang |first=JH |last2=Nichogiannopoulou, A |last3=Wu, L |last4=Sun, L |last5=Sharpe, AH |last6=Bigby, M |last7=Georgopoulos, K |date=Dec 1996 |title=Selective defects in the development of the fetal and adult lymphoid system in mice with an Ikaros null mutation. |journal=Immunity |volume=5 |issue=6 |pages=537–49 |doi=10.1016/s1074-7613(00)80269-1 |pmid=8986714 |doi-access=free}}</ref> Ikaros has six [[zinc finger]]s domains, four are conserved [[DNA-binding domain]] and two are for [[Protein dimer|dimer]]ization.<ref>{{Cite journal |last=Sun |first=L |last2=Liu, A |last3=Georgopoulos, K |date=Oct 1, 1996 |title=Zinc finger-mediated protein interactions modulate Ikaros activity, a molecular control of lymphocyte development. |journal=The EMBO Journal |volume=15 |issue=19 |pages=5358–69 |doi=10.1002/j.1460-2075.1996.tb00920.x |pmc=452279 |pmid=8895580}}</ref> Very important finding is, that different zinc fingers are involved in binding to different place in DNA and this is the reason for pleiotropic effect of Ikaros and different involvement in cancer, but mainly are mutations associated with [[BCR-Abl]] patients and it is bad prognostic marker.<ref>{{Cite journal |last=Schjerven |first=H |last2=McLaughlin, J |last3=Arenzana, TL |last4=Frietze, S |last5=Cheng, D |last6=Wadsworth, SE |last7=Lawson, GW |last8=Bensinger, SJ |last9=Farnham, PJ |last10=Witte, ON |last11=Smale, ST |date=Oct 2013 |title=Selective regulation of lymphopoiesis and leukemogenesis by individual zinc fingers of Ikaros. |journal=Nature Immunology |volume=14 |issue=10 |pages=1073–83 |doi=10.1038/ni.2707 |pmc=3800053 |pmid=24013668}}</ref>

== Other animals ==
In some [[vertebrate]]s, haematopoiesis can occur wherever there is a loose [[Stromal cell|stroma]] of connective tissue and slow blood supply, such as the [[Gut (zoology)|gut]], [[spleen]] or [[kidney]].<ref>{{Cite journal |last=Zon |first=LI |date=Oct 15, 1995 |title=Developmental biology of hematopoiesis. |journal=Blood |type=Review |volume=86 |issue=8 |pages=2876–91 |doi=10.1182/blood.V86.8.2876.2876 |pmid=7579378 |doi-access=free}}</ref>

Unlike eutherian mammals, the liver of newborn marsupials is actively haematopoietic.<ref>Old JM (2016). Haematopoiesis in marsupials. Developmental and Comparative Immunology. 58, 40-46. DOI: 10.1016/j.dci.2015.11.009</ref><ref>Old JM, Deane EM (2000). Development of the immune system and immunological protection in marsupial pouch young. Developmental and Comparative Immunology. 24(5), 445-454. DOI: 10.1016/S0145-305X(00)00008-2</ref><ref>Old JM, Deane EM (2003). The lymphoid and immunohaematopoietic tissues of the embryonic brushtail possum (''Trichosurus vulpecula''). Anatomy and Embryology (now called Brain Structure and Function). 206(3), 193-197. DOI: 10.1007/s00429-002-0285-2</ref><ref>Old JM, [[Lynne Selwood|Selwood L]], Deane EM (2003). A histological investigation of the lymphoid and immunohaematopoietic tissues of the adult stripe-faced dunnart (''Sminthopsis macroura''). Cells Tissues Organs. 173(2), 115-121. DOI: 10.1159/000068946</ref>

==See also==
* [[Clonal hematopoiesis]]
* [[Erythropoiesis-stimulating agents]]
* Haematopoietic stimulants:
** [[Granulocyte colony-stimulating factor]]
** [[Granulocyte macrophage colony-stimulating factor]]
* [[Leukocyte extravasation]]

==References==
{{reflist}}

==Further reading==
* {{Cite book |url=https://books.google.com/books?id=tUsSmZwW_9MC |title=Hematopoietic stem cell development |publisher=Springer |year=2006 |isbn=978-0-306-47872-7 |editor-last=Godin, Isabelle |editor-last2=Cumano, Ana}}

==External links==
{{Scholia|topic}}
* [https://www.genome.jp/kegg-bin/show_pathway?map=hsa04640&show_description=show Hematopoietic cell lineage] in [[KEGG]]
* [http://www.histology-world.com/photoalbum/thumbnails.php?album=65 Hematopoiesis and bone marrow histology]

{{Immune system}}
{{Lymphatic system}}
{{Blood physiology}}
{{Cytokines}}
{{Authority control}}

[[Category:Hematopoiesis]]
[[Category:Histology]]