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{{Infobox cell
| Name = Hematopoietic stem cell
| Latin =
| Image = Hematopoiesis simple.svg
| Caption = Overview of normal human haematopoiesis
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}}
'''Hematopoietic stem cells''' ('''HSCs''') are the [[stem cell]]s<ref name="Monga">{{cite journal | vauthors = Monga I, Kaur K, Dhanda S| 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 | date = March 2022 | pmid = 35265979 | doi = 10.1093/bfgp/elac002}}</ref> that give rise to other [[blood cell]]s. This process is called [[haematopoiesis]].<ref name="Birbrair n/a–n/a">{{cite journal | vauthors = Birbrair A, Frenette PS | title = Niche heterogeneity in the bone marrow | journal = Annals of the New York Academy of Sciences | volume = 1370 | issue = 1 | pages = 82–96 | date = April 2016 | pmid = 27015419 | pmc = 4938003 | doi = 10.1111/nyas.13016 | bibcode = 2016NYASA1370...82B }}</ref> In [[vertebrate]]s, the
[[Haematopoiesis]] is the process by which all mature blood cells are produced. It must balance enormous production needs (the average person produces more than 500 billion blood cells every day) with the need to regulate the number of each blood cell type in the circulation. In vertebrates, the vast majority of hematopoiesis occurs in the bone marrow and is derived from a limited number of hematopoietic stem cells that are multipotent and capable of extensive [[stem cell self-renewal|self-renewal]].
Hematopoietic stem cells give rise to different types of blood cells, in lines called [[Myelopoiesis|myeloid]] and [[Lymphopoiesis|lymphoid]]. Myeloid and lymphoid lineages both are involved in [[dendritic cell]] formation. Myeloid cells include [[monocyte]]s, [[macrophage]]s, [[neutrophil granulocyte|neutrophil]]s, [[basophil granulocyte|basophil]]s, [[eosinophil granulocyte|eosinophil]]s, [[erythrocyte]]s, and [[megakaryocyte]]s to [[platelet]]s. Lymphoid cells include [[T cell]]s, [[B cell]]s, [[natural killer cell]]s, and [[innate lymphoid cell]]s.
The definition of hematopoietic stem cell has developed since they were first discovered in 1961.<ref>{{cite journal | vauthors = Till JE, McCULLOCH EA | title = A direct measurement of the radiation sensitivity of normal mouse bone marrow cells | journal = Radiation Research | volume = 14 | issue = 2 | pages = 213–22 | date = February 1961 | pmid = 13776896 | doi = 10.2307/3570892 | hdl-access = free | bibcode = 1961RadR...14..213T | jstor = 3570892 | hdl = 1807/2781 }}</ref> The hematopoietic tissue contains cells with long-term and short-term regeneration capacities and committed [[multipotent]], [[oligopotency|oligopotent]], and [[Unipotency|unipotent]] progenitors. Hematopoietic stem cells constitute 1:10,000 of cells in [[myeloid tissue]].
HSC transplants are used in the treatment of cancers and other immune system disorders
== Structure ==
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===Location===
The very first hematopoietic stem cells during (mouse and human) embryonic development are found in [[aorta-gonad-mesonephros]] region and the vitelline and umbilical arteries.<ref>{{cite journal | vauthors = de Bruijn MF, Speck NA, Peeters MC, Dzierzak E | title = Definitive hematopoietic stem cells first develop within the major arterial regions of the mouse embryo | journal = The EMBO Journal | volume = 19 | issue = 11 | pages = 2465–2474 | date = June 2000 | pmid = 10835345 | pmc = 212758 | doi = 10.1093/emboj/19.11.2465 }}</ref><ref>{{cite journal | vauthors = Medvinsky A, Dzierzak E | title = Definitive hematopoiesis is autonomously initiated by the AGM region | journal = Cell | volume = 86 | issue = 6 | pages = 897–906 | date = September 1996 | pmid = 8808625 | doi = 10.1016/s0092-8674(00)80165-8 | hdl = 1765/57137 | s2cid = 3330712 | url = http://repub.eur.nl/pub/57137 | hdl-access = free }}</ref><ref>{{cite journal | vauthors = Ivanovs A, Rybtsov S, Welch L, Anderson RA, Turner ML, Medvinsky A | title = Highly potent human hematopoietic stem cells first emerge in the intraembryonic aorta-gonad-mesonephros region | journal = The Journal of Experimental Medicine | volume = 208 | issue = 12 | pages = 2417–2427 | date = November 2011 | pmid = 22042975 | pmc = 3256972 | doi = 10.1084/jem.20111688 }}</ref> Slightly later, HSCs are also found in the placenta, yolk sac, embryonic head, and fetal liver.<ref name=":0" /><ref
Stem and progenitor cells can be taken from the pelvis, at the iliac crest, using a needle and syringe.<ref>{{cite web|title=Bone Marrow Transplant Process|url=http://www.mayoclinic.org/departments-centers/transplant-center/bone-marrow-transplant/preparing/process|website=Mayo Clinic|access-date=18 March 2015}}</ref> The cells can be removed as liquid (to perform a smear to look at the cell morphology) or they can be removed via a core biopsy (to maintain the architecture or relationship of the cells to each other and to the bone).{{citation needed|date=March 2013}}
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* Colony-forming unit–[[granulocyte]]-[[macrophage]] ([[CFU-GM]])
* Colony-forming unit–[[megakaryocyte]] ([[CFU-Meg]])
* Colony-forming unit–[[basophil]] ([[CFU-
* Colony-forming unit–[[eosinophil]] ([[CFU-Eos]])
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===Isolating stem cells===
{{Further|Techniques to isolate haematopoietic stem cells}}
Since hematopoietic stem cells cannot be isolated as a pure population, it is not possible to identify them in a microscope.{{Citation needed|date=July 2019}} Hematopoietic stem cells can be identified or isolated by the use of [[flow cytometry]] where the combination of several different cell surface markers (particularly [[CD34]]) are used to separate the rare
== Function ==
[[File:Hematopoiesis (human) diagram en.svg|thumb|Diagram of cells that arise from
=== Haematopoiesis ===
{{Main|Haematopoiesis}}Hematopoietic stem cells are essential to haematopoiesis, the formation of the cells within blood. Hematopoietic stem cells can replenish all blood cell types (i.e., are [[Cell potency#Multipotency|multipotent]]) and self-renew. A small number of
Stem cell self-renewal is thought to occur in the [[stem cell niche]] in the bone marrow, and it is reasonable to assume that key signals present in this niche will be important in self-renewal.<ref name="Birbrair n/a–n/a" /> There is much interest in the environmental and molecular requirements for HSC self-renewal, as understanding the ability of HSC to replenish themselves will eventually allow the generation of expanded populations of HSC ''in vitro'' that can be used therapeutically.
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===Transplant===
{{Main|Hematopoietic stem cell transplantation}}
Hematopoietic stem cell transplantation (HSCT) is the transplantation of [[multipotent hematopoietic stem cell]]s, usually derived from bone marrow, peripheral blood, or umbilical cord blood.<ref name="HSCT2">{{cite journal | vauthors = Felfly H, Haddad GG | title = Hematopoietic stem cells: potential new applications for translational medicine | journal = Journal of Stem Cells | volume = 9 | issue = 3 | pages = 163–197 | date = 2014 | pmid = 25157450 }}</ref><ref name="HSCT1">{{cite journal | vauthors = Park B, Yoo KH, Kim C | title = Hematopoietic stem cell expansion and generation: the ways to make a breakthrough | journal = Blood Research | volume = 50 | issue = 4 | pages = 194–203 | date = December 2015 | pmid = 26770947 | pmc = 4705045 | doi = 10.5045/br.2015.50.4.194 }}</ref><ref
It is most often performed for patients with certain [[cancer]]s of the [[blood]] or [[bone marrow]], such as [[multiple myeloma]] or [[leukemia]].<ref name="HSCT1" /> In these cases, the recipient's immune system is usually destroyed with radiation or chemotherapy before the transplantation. Infection and [[graft-versus-host disease]] are major complications of [[Allotransplantation|allogeneic]] HSCT.<ref name="HSCT1" />
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Hematopoietic stem cell transplantation remains a dangerous procedure with many possible complications; it is reserved for patients with life-threatening diseases. As survival following the procedure has increased, its use has expanded beyond cancer to [[autoimmune diseases]]<ref>{{cite journal | vauthors = Tyndall A, Fassas A, Passweg J, Ruiz de Elvira C, Attal M, Brooks P, Black C, Durez P, Finke J, Forman S, Fouillard L, Furst D, Holmes J, Joske D, Jouet J, Kötter I, Locatelli F, Prentice H, Marmont AM, McSweeney P, Musso M, Peter HH, Snowden JA, Sullivan K, Gratwohl A | display-authors = 6 | title = Autologous haematopoietic stem cell transplants for autoimmune disease--feasibility and transplant-related mortality. Autoimmune Disease and Lymphoma Working Parties of the European Group for Blood and Marrow Transplantation, the European League Against Rheumatism and the International Stem Cell Project for Autoimmune Disease | journal = Bone Marrow Transplantation | volume = 24 | issue = 7 | pages = 729–734 | date = October 1999 | pmid = 10516675 | doi = 10.1038/sj.bmt.1701987 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Burt RK, Loh Y, Pearce W, Beohar N, Barr WG, Craig R, Wen Y, Rapp JA, Kessler J | display-authors = 6 | title = Clinical applications of blood-derived and marrow-derived stem cells for nonmalignant diseases | journal = JAMA | volume = 299 | issue = 8 | pages = 925–936 | date = February 2008 | pmid = 18314435 | doi = 10.1001/jama.299.8.925 | doi-access = free }}</ref> and hereditary [[skeletal dysplasia]]s; notably [[malignant infantile osteopetrosis]]<ref name="elsobky2017">{{cite journal | vauthors = El-Sobky TA, El-Haddad A, Elsobky E, Elsayed SM, Sakr HM |title=Reversal of skeletal radiographic pathology in a case of malignant infantile osteopetrosis following hematopoietic stem cell transplantation |journal=The Egyptian Journal of Radiology and Nuclear Medicine |date=March 2017 |volume=48 |issue=1 |pages=237–243 |doi=10.1016/j.ejrnm.2016.12.013 |doi-access=free | name-list-style=vanc}}</ref><ref name="Hashemi2015">{{cite journal | vauthors = Hashemi Taheri AP, Radmard AR, Kooraki S, Behfar M, Pak N, Hamidieh AA, Ghavamzadeh A | title = Radiologic resolution of malignant infantile osteopetrosis skeletal changes following hematopoietic stem cell transplantation | journal = Pediatric Blood & Cancer | volume = 62 | issue = 9 | pages = 1645–1649 | date = September 2015 | pmid = 25820806 | doi = 10.1002/pbc.25524 | name-list-style = vanc | s2cid = 11287381 }}</ref> and [[mucopolysaccharidosis]].<ref>{{cite journal | vauthors = Langereis EJ, den Os MM, Breen C, Jones SA, Knaven OC, Mercer J, Miller WP, Kelly PM, Kennedy J, Ketterl TG, O'Meara A, Orchard PJ, Lund TC, van Rijn RR, Sakkers RJ, White KK, Wijburg FA | display-authors = 6 | title = Progression of Hip Dysplasia in Mucopolysaccharidosis Type I Hurler After Successful Hematopoietic Stem Cell Transplantation | journal = The Journal of Bone and Joint Surgery. American Volume | volume = 98 | issue = 5 | pages = 386–395 | date = March 2016 | pmid = 26935461 | doi = 10.2106/JBJS.O.00601 | name-list-style = vanc }}</ref>
Stem cells can be used to regenerate different types of tissues. HCT is an established as therapy for chronic myeloid leukemia, acute lymphatic leukemia, aplastic anemia, and hemoglobinopathies, in addition to acute myeloid leukemia and primary immune deficiencies. Hematopoietic system regeneration is typically achieved within 2–4 weeks post-chemo- or irradiation therapy and HCT. HSCs are being clinically tested for their use in non-hematopoietic tissue regeneration.<ref>{{Cite journal |last1=Müller |first1=Albrecht M. |last2=Huppertz |first2=Sascha |last3=Henschler |first3=Reinhard |date=2016-07-26 |title=Hematopoietic Stem Cells in Regenerative Medicine: Astray or on the Path? |url=https://doi.org/10.1159/000447748 |journal=Transfusion Medicine and Hemotherapy |volume=43 |issue=4 |pages=247–254 |doi=10.1159/000447748 |pmid=27721700 |issn=1660-3796|pmc=5040947 }}</ref>
=== Aging of hematopoietic stem cells ===
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DNA strand breaks accumulate in long term hematopoietic stem cells during aging.<ref name="Beerman">{{cite journal | vauthors = Beerman I, Seita J, Inlay MA, Weissman IL, Rossi DJ | title = Quiescent hematopoietic stem cells accumulate DNA damage during aging that is repaired upon entry into cell cycle | journal = Cell Stem Cell | volume = 15 | issue = 1 | pages = 37–50 | date = July 2014 | pmid = 24813857 | pmc = 4082747 | doi = 10.1016/j.stem.2014.04.016 }}</ref> This accumulation is associated with a broad attenuation of [[DNA repair]] and response pathways that depends on HSC quiescence.<ref name="Beerman" /> [[Non-homologous end joining]] (NHEJ) is a pathway that repairs double-strand breaks in DNA. NHEJ is referred to as "non-homologous" because the break ends are directly ligated without the need for a homologous template. The NHEJ pathway depends on several proteins including [[LIG4|ligase 4]], [[DNA polymerase mu]] and [[Non-homologous end-joining factor 1|NHEJ factor 1]] (NHEJ1, also known as Cernunnos or XLF).
DNA ligase 4 (Lig4) has a highly specific role in the repair of double-strand breaks by NHEJ. Lig4 deficiency in the mouse causes a progressive loss of
In polymerase mu mutant mice, hematopoietic cell development is defective in several peripheral and bone marrow cell populations with about a 40% decrease in bone marrow cell number that includes several hematopoietic lineages.<ref name="pmid19229323">{{cite journal | vauthors = Lucas D, Escudero B, Ligos JM, Segovia JC, Estrada JC, Terrados G, Blanco L, Samper E, Bernad A | display-authors = 6 | title = Altered hematopoiesis in mice lacking DNA polymerase mu is due to inefficient double-strand break repair | journal = PLOS Genetics | volume = 5 | issue = 2 | pages = e1000389 | date = February 2009 | pmid = 19229323 | pmc = 2638008 | doi = 10.1371/journal.pgen.1000389 | doi-access = free }}</ref> Expansion potential of hematopoietic progenitor cells is also reduced. These characteristics correlate with reduced ability to repair double-strand breaks in hematopoietic tissue.
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===Behavior in culture===
A ''cobblestone area-forming cell (CAFC)'' [[assay]] is a cell culture-based empirical assay. When plated onto a confluent culture of stromal [[feeder layer]],<ref>{{Cite journal |last1=Llames |first1=Sara |last2=Garcia-Perez |first2=Eva |last3=Meana |first3=Alvaro |last4=Larcher |first4=Fernando |last5=del Rio |first5=Marcela |date=2015 |title=Feeder Layer Cell Actions and Applications |journal=Tissue Eng Part B Rev |volume=21 |issue=4 |pages=345–353 |doi=10.1089/ten.teb.2014.0547 |pmc=4533020 |pmid=25659081 }}</ref> a fraction of
=== Repopulation kinetics ===
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The reconstitution kinetics are very heterogeneous. However, using [[symbolic dynamics]], one can show that they fall into a limited number of classes.<ref>{{cite journal | vauthors = Sieburg HB, Müller-Sieburg CE | title = Classification of short kinetics by shape | journal = In Silico Biology | volume = 4 | issue = 2 | pages = 209–17 | year = 2004 | pmid = 15107024 }}</ref> To prove this, several hundred experimental repopulation kinetics from clonal Thy-1<sup>lo</sup> SCA-1<sup>+</sup> lin<sup>−</sup>(B220, CD4, CD8, Gr-1, Mac-1 and Ter-119)<ref>{{cite journal |last1=Challen |first1=Grant A. |last2=Boles |first2=Nathan |last3=Lin |first3=Kuan-Yin K. |last4=Goodell |first4=Margaret A. |title=Mouse hematopoietic stem cell identification and analysis |journal=Cytometry Part A |date=January 2009 |volume=75A |issue=1 |pages=14–24 |doi=10.1002/cyto.a.20674 |pmid=19023891|pmc=2640229 }}</ref> c-kit<sup>+</sup> HSC were translated into symbolic sequences by assigning the symbols "+", "-", "~" whenever two successive measurements of the percent donor-type cells have a positive, negative, or unchanged slope, respectively. By using the [[Hamming distance]], the repopulation patterns were subjected to cluster analysis yielding 16 distinct groups of kinetics. To finish the empirical proof, the [[Additive smoothing|Laplace add-one approach]] was used to determine that the probability of finding kinetics not contained in these 16 groups is very small. By corollary, this result shows that the hematopoietic stem cell compartment is also heterogeneous by dynamical criteria.
It was originally believed that all
Subsequently, other groups confirmed and highlighted the original findings.<ref name="Schroeder, T 2010">{{cite journal | vauthors = Schroeder T | title = Hematopoietic stem cell heterogeneity: subtypes, not unpredictable behavior | journal = Cell Stem Cell | volume = 6 | issue = 3 | pages = 203–7 | date = March 2010 | pmid = 20207223 | doi = 10.1016/j.stem.2010.02.006 | doi-access = free }}</ref> For example, the Eaves group confirmed in 2007 that repopulation kinetics, long-term self-renewal capacity, and My-bi and Ly-bi are stably inherited intrinsic HSC properties.<ref name="ReferenceC">{{cite journal | vauthors = Dykstra B, Kent D, Bowie M, McCaffrey L, Hamilton M, Lyons K, Lee SJ, Brinkman R, Eaves C | display-authors = 6 | title = Long-term propagation of distinct hematopoietic differentiation programs in vivo | journal = Cell Stem Cell | volume = 1 | issue = 2 | pages = 218–29 | date = August 2007 | pmid = 18371352 | doi = 10.1016/j.stem.2007.05.015 | doi-access = free }}</ref> In 2010, the Goodell group provided additional insights about the molecular basis of lineage bias in [[side population]] (SP) SCA-1<sup>+</sup> lin<sup>−</sup> c-kit<sup>+</sup> HSC.<ref name="Challen, G. 2010">{{cite journal | vauthors = Challen GA, Boles NC, Chambers SM, Goodell MA | title = Distinct hematopoietic stem cell subtypes are differentially regulated by TGF-beta1 | journal = Cell Stem Cell | volume = 6 | issue = 3 | pages = 265–78 | date = March 2010 | pmid = 20207229 | pmc = 2837284 | doi = 10.1016/j.stem.2010.02.002 }}</ref> As previously shown for IL-7 signaling, it was found that a member of the [[transforming growth factor]] family (TGF-beta) induces and inhibits the proliferation of My-bi and Ly-bi HSC, respectively.
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