Haematopoiesis: Difference between revisions

[[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. This phenomenon is called [[Asymmetric cell division|asymmetric division.]]<ref>{{cite journal|last=Morrison|first=J.|author2=Judith Kimble|title=Asymmetric and symmetric stem-cell divisions in development and cancer|doi=10.1038/nature04956|pmid=16810241|journal=Nature|volume=441|issue=7097|pages=1068–74|year=2006|bibcode=2006Natur.441.1068M|hdl=2027.42/62868|s2cid=715049|url=https://deepblue.lib.umich.edu/bitstream/2027.42/62868/1/nature04956.pdf|hdl-access=free}}</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.

* [[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 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]].

[[MegakaryocytopoiesisThrombopoiesis]] is haematopoiesis of megakaryocytes.{{cn[[Platelet|date=Decemberthrombocytes 2021}}(platelets)]].

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 web |last1=Singh |first1=Ranbir |last2=Soman-Faulkner |first2=Kristina |last3=Sugumar |first3=Kavin |title=Embryology, Hematopoiesis |url=https://www.ncbi.nlm.nih.gov/books/NBK544245/ |website=NCBI |publisher=StatPearls |access-date=4 September 2022}}</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>

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|chapter=Stochasticity and determinism in models of hematopoiesis|journal=Advances in Experimental Medicine and Biology|volume=844|pages=119–152|doi=10.1007/978-1-4939-2095-2_7|issn=0065-2598|pmid=25480640|isbn=978-1-4939-2094-5}}</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|title = Transcriptome-wide noise controls lineage choice in mammalian progenitor cells|journal = Nature|pages = 544–547|volume = 453|issue = 7194|doi = 10.1038/nature06965|first1 = Hannah H.|last1 = Chang|first2 = Martin|last2 = Hemberg|first3 = Mauricio|last3 = Barahona|first4 = Donald E.|last4 = Ingber|first5 = Sui|last5 = Huang|pmid=18497826|pmc = 5546414|bibcode = 2008Natur.453..544C|year = 2008}}</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|author2=Alenazi, BQ |author3=Ahmad, SY |author4=Salem, ML |author5=Al-Jabri, AA |author6= Wyse, RK |title=The haemopoietic stem cell: between apoptosis and self renewal.|journal=The Yale Journal of Biology and Medicine|date=Mar 2009|volume=82|issue=1|pages=7–18|pmid=19325941 |pmc=2660591}}</ref>

[[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 |author1=Rod Flower |author2=Humphrey P. Rang |author3=Maureen M. Dale |author4=Ritter, James M. |title=Rang & Dale's pharmacology |publisher=Churchill Livingstone |location=Edinburgh |year=2007 |isbn=978-0-443-06911-6 }}</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.|author2=A. C. Newland|title=Haemopoietic growth factors.|journal=Postgrad Med J|volume=73|issue=858|pages=215–221|doi=10.1136/pgmj.73.858.215|pmid=9156123|pmc=2431295|year=1997}}</ref> These stimulate [[granulocyte]] formation and are active on either [[progenitor cells]] or end product cells.

----{{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|author2=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>

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 |author2=Alonzo, TA |author3=Gerbing, RB |author4=Pollard, J |author5=Stirewalt, DL |author6=Hurwitz, C |author7=Heerema, NA |author8=Hirsch, B |author9=Raimondi, SC |author10=Lange, B |author11=Franklin, JL |author12=Radich, JP |author13=Meshinchi, S|title=Prevalence and prognostic implications of CEBPA mutations in pediatric acute myeloid leukemia (AML): a report from the Children's Oncology Group.|journal=Blood|date=Jun 25, 2009|volume=113|issue=26|pages=6558–66|pmid=19304957|doi=10.1182/blood-2008-10-184747|pmc=2943755}}</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 |url=https://doi.org/10.1182/blood-2015-07-607945 |journal=Blood |volume=127 |issue=10 |pages=1242–1248 |doi=10.1182/blood-2015-07-607945 |issn=0006-4971}}</ref>

An example is [[PAX5]] factor, which is important in B cell development and associated with lymphomas.<ref>{{cite journal |last1=O'Brien |first1=P |last2=Morin |first2=P, Jr |last3=Ouellette |first3=RJ |last4=Robichaud |first4=GA |title=The Pax-5 gene: a pluripotent regulator of B-cell differentiation and cancer disease |journal=Cancer Research |date=Dec 15, 2011 |volume=71 |issue=24 |pages=7345–50 |pmid=22127921 |doi=10.1158/0008-5472.CAN-11-1874|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|author2=Jochum, W|author3=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|author2=Nichogiannopoulou, A|author3=Wu, L|author4=Sun, L|author5=Sharpe, AH|author6=Bigby, M|author7=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|author2=Liu, A |author3=Georgopoulos, K |title=Zinc finger-mediated protein interactions modulate Ikaros activity, a molecular control of lymphocyte development.|journal=The EMBO Journal|date=Oct 1, 1996|volume=15|issue=19|pages=5358–69|doi=10.1002/j.1460-2075.1996.tb00920.x|pmid=8895580|pmc=452279}}</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 |author2=McLaughlin, J |author3=Arenzana, TL |author4=Frietze, S |author5=Cheng, D |author6=Wadsworth, SE |author7=Lawson, GW |author8=Bensinger, SJ |author9=Farnham, PJ |author10=Witte, ON |author11=Smale, ST|title=Selective regulation of lymphopoiesis and leukemogenesis by individual zinc fingers of Ikaros.|journal=Nature Immunology|date=Oct 2013|volume=14|issue=10|pages=1073–83|pmid=24013668|doi=10.1038/ni.2707|pmc=3800053}}</ref>