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Haematopoietic stem cells: past, present and future

Haematopoietic stem cells: past, present and future Citation: Cell Death Discovery (2017) 3, 17002; doi:10.1038/cddiscovery.2017.2 OPEN Official journal of the Cell Death Differentiation Association www.nature.com/cddiscovery REVIEW 1,2 1,2 Ashley P Ng and Warren S Alexander The discovery and characterisation of haematopoietic stem cells has required decades of research. The identification of adult bone marrow as a source of haematopoietic cells capable of protecting an organism from otherwise lethal irradiation led to the intense search for their identity and characteristics. Using functional assays along with evolving techniques for isolation of haematopoietic cells, haematopoietic stem cell populations were able to be enriched and their characteristics analysed. The key haematopoietic stem cell characteristics of pluripotentiality and the ability for self-renewal have emerged as characteristics of several haematopoietic stem cell populations, including those that have recently challenged the conventional concepts of the haematopoietic hierarchy. Human allogeneic stem cell therapy relies on these functional characteristics of haematopoietic stem cells that can be isolated from peripheral blood, bone marrow or cord blood, with the additional requirement that immunological barriers need to be overcome to allow sustained engraftment while minimising risk of graft-versus-host disease developing in the recipient of transplanted stem cells. Current and future research will continue to focus on the identification of haematopoietic stem cell regulators and methods for in vitro and in vivo stem cell manipulation, including genome editing, to expand the scope, potential and safety of therapy using haematopoietic stem cells. Cell Death Discovery (2017) 3, 17002; doi:10.1038/cddiscovery.2017.2; published online 6 February 2017 KEY-POINTS Definitive haematopoiesis in the embryo begins with the emergence of the first identifiable HSC in the aorto-gonado- 6,7 mesonephros region. Thereafter, haematopoiesis shifts to the Haematopoietic stem cells are rare cells with characteristics of fetal liver, and subsequently to the bone marrow, where HSCs will pluripotency and self-renewal that are capable of generating an 8,9 reside for the life of the mammalian organism (Figure 1). entire haematopoeitic system. Haematopoietic stem cells have been identified at defined stages of embryonic development and several subsets have IDENTIFICATION OF HSCS been characterised in adult haematopoiesis. The relative contribution of haematopoietic stem cells to steady- It became apparent, initially through work that sought to state and stress haematopoiesis remains controversial. characterise radiation sensitivity, that donor adult bone marrow Allogeneic haematopoietic stem cell transplantation therapy transplanted into syngeneic irradiated murine recipients was in human requires significant immunological barriers to be capable of protecting the recipients from lethal irradiation by overcome. regenerating (reconstituting) the irradiation-ablated haematopoie- Current and future research aims to identify key stem cell tic system. This research was crucial in the development of the concept of HSC as cells in the bone marrow capable of generating regulators and methods for in vitro and in vivo stem cell manipulation including genome editing. the complete blood cell system, although at this time the specific cell had yet to be isolated and characterised. In these early experiments, donor-derived clonogenic colonies Haematopoietic stem cells (HSC) are the architects of definitive of multiple haematopoietic lineages were able to be macro- haematopoiesis, that is, blood cell production that occurs 10,11 scopically identified in the spleen of transplanted recipients. continuously during the life of an organism. Each HSC is These spleen colony-forming units, although not definitive HSCs, programmed to allow efficient production of the cellular blood were nevertheless useful in allowing characterisation of progenitor components with a manifest purpose that has been shaped by cells responsible for haematopoietic reconstitution. Specific evolution: from red cells that allow efficient carriage of oxygen, progenitor cells appeared to possess the ability to form multiple megakaryocytes and their platelet progeny that interact with haematopoietic lineages from within the one colony (multi- blood vessels and soluble coagulation factors to regulate clotting, potency), while others appeared able to form daughter cells that to the cells of the innate and acquired immune system that act retained the characteristics of the original parental cell (self- against microbial attack. HSCs are defined by their pluripotenti- renewal). These two important characteristics ultimately came to ality, the capacity for a single HSC to generate any and all of the diverse mature functional haematopoietic cell types. Key genes be recognised as definitive characteristics of HSC. and select genetic programmes are invoked for the maintenance, The identification and characterisation of HSCs ultimately required strategies to separate these rare bone marrow cells from or self-renewal of HSCs and for the formation of the specific 1–5 haematopoietic lineages. more numerous cellular components. Functional competitive 1 2 The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, VIC, Australia and Department of Medical Biology, The University of Melbourne, Parkville, VIC, Australia. Correspondence: AP Ng ([email protected]) Received 21 December 2016; accepted 29 December 2016; Edited by A Rufini Haematopoietic stem cells: discovery to the clinic AP Ng and WS Alexander Figure 2. Immunophenotypic markers of adult murine HSCs and Figure 1. The journey from fetal to adult haematopoiesis adapted ‘lineage-restricted’ HSC populations. See references in main text. from Dzierzak and Speck. AGM, aorto-gonado-mesonephros; PsP, para-aortic-splanchnopleura. See references in main text. state. However, other studies have yielded apparently conflicting results on the relative contribution of HSCs to steady state and 35,36 repopulating unit assays estimated the frequency of these rare stress haematopoiesis, a current controversy that remains to cells as one in 10 000 cells in bone marrow. Like the proverbial be resolved. search for the needle in a haystack, HSCs were eventually In the setting of bone marrow transplantation, which is isolated with increasing purity based on physical properties, such dependent on HSCs to sustainably reconstitute haematopoiesis, as Hoescht 33342 supravital dye exclusion, resistance to further refinement of cell surface markers have also identified 15 16 5-fluorouracil or γ-irradiation. Ultimately, however, it was the specific subsets of HSCs with more limited capacity for self- application of flow cytometry and the use of specific cell surface renewal, yet important for maintaining haematopoiesis in the 37,38 antigen markers that led to the ability to prospectively identify short and intermediate terms after transplantation. Stem cells cell populations able to reconstitute multiple lineages upon capable of true long-term reconstitution with durable self-renewal transplantation, and capable of self-renewal as judged by serial potential do appear to be a very rare but essential cell popu- 39–41 transplantation assays. These cell populations, enriched for HSCs, lation required for long-term haematopoietic engraftment were notable for their lack of mature lineage antigen expression, (Figure 2). and expression of antigens such as cKit, the cellular receptor for 18,19 the cytokine stem cell factor. HSCs were found to possess unique properties that set them BONE MARROW TRANSPLANTATION AS THERAPY apart from other blood-forming progenitor cells. In addition to the Although murine haematopoiesis reflects human haematopoiesis properties of pluripotency and self-renewal, adult long-term HSCs in many ways, the immunophenotypic markers of human HSCs − + − were found to reside in a specific niche environment in the bone (Lineage CD34 CD38 ) differ from functionally similar murine marrow, which was closely associated with endosteum, and counterparts. Unlike inbred genetically and immunologically where they exist in conditions of relative hypoxia. Here, HSC identical mouse strains, successful allogeneic transplantation exists predominantly in a non-replicative and quiescent state, in therapy in humans requires significant immunological barriers to 23,24 which signalling by the cytokine thrombopoietin and the be overcome. The discovery of the HLA system of MHC class I and presence of megakaryocytes are recognised to have an important II receptors, which engage T-cell antigen receptors, allows 25–27 role. In contexts that place the haematopoietic system under histocompatible matching of donors and recipients. This is stress, such as chronic infection, these quiescent stem cells are supplemented with the use of immunosuppression during and recruited into cell cycle, for example, via interferon signalling, after the transplantation of allogeneic stem cells from volunteer- which is associated with a numerical increase in downstream related and -unrelated donors. Advancement of stem cell progenitor cells. Evidence increasingly suggests that lineage transplantation therapy has focussed on research to broaden specification can occur very early in the haematopoietic hierarchy the availability of donors to patients. Use of cord blood units as a 29–32 43,44 in immunophenotypically defined ‘stem cell’ populations source of stem cells and recently developed conditioning and (Figure 2), supporting findings that self-renewing lineage- immunosuppressive regimens have allowed haploidentical restricted progenitors may emerge directly from HSC. A transplantation to become a therapeutic reality while limiting significant degree of complexity may therefore exist in the the immunological consequence of graft-versus-host disease. pathways via which mature haematopoietic lineages develop from These approaches are increasingly making the option of HSC and progenitor populations. More direct pathways from HSC allogeneic transplantation available to patients who otherwise to specific mature cells may coexist alongside traditional models do not have a matched-related or volunteer-unrelated donor of progenitor population hierarchies. Recent evidence from clonal source of stem cells (Figure 3). dynamic studies tracing the origin of blood cells over time has suggested that steady-state blood cell maintenance does not THE FUTURE incessantly call upon the quiescent HSCs to enter into cell cycle, but rather, successive recruitment of long-lived progenitor Research defining the nature and regulation of HSCs has populations appears to primarily maintain blood cells at steady allowed regulators of blood cell production to be manipulated Cell Death Discovery (2017) 17002 Official journal of the Cell Death Differentiation Association Haematopoietic stem cells: discovery to the clinic AP Ng and WS Alexander ACKNOWLEDGEMENTS An earlier version of this manuscript was published in Australian Biochemist (Vol. 47, No. 1, April 2016). This work was supported by the Australian National Health and Medical Research Council Project Grant (1060179; to APN), Program Grant (1016647), Fellowships (1058344; to WSA), Independent Research Institutes Infrastructure Support Scheme Grant (9000220) and a Victorian State Government Operational Infrastructure Support Grant. COMPETING INTERESTS The authors declare no conflict of interest. REFERENCES 1 Ivanova NB, Dimos JT, Schaniel C, Hackney JA, Moore KA, Lemischka IR. A stem cell molecular signature. Science 2002; 298: 601–604. 2 Mercer EM, Lin YC, Murre C. Factors and networks that underpin early hemato- poiesis. Semin Immunol 2011; 23:317–325. 3 Novershtern N, Subramanian A, Lawton LN, Mak RH, Haining WN, McConkey ME et al. Densely interconnected transcriptional circuits control cell states in human hematopoiesis. Cell 2011; 144:296–309. Figure 3. Human HSC transplantation therapy. HLA-matched adult, 4 Moignard V, Macaulay IC, Swiers G, Buettner F, Schütte J, Calero-Nieto FJ et al. cord blood or haploidentical adult donor stem and progenitor cells Characterization of transcriptional networks in blood stem and progenitor cells are transplanted intravenously into a recipient following condition- using high-throughput single-cell gene expression analysis. Nat Cell Biol 2013; 15: ing therapy to permit engraftment of donor marrow into the 363–372. recipient. Immune suppression is administered to prevent acute 5 Riddell J, Gazit R, Garrison BS, Guo G, Saadatpour A, Mandal PK et al. Repro- graft-versus-host disease. gramming committed murine blood cells to induced hematopoietic stem cells with defined factors. Cell 2014; 157:549–564. 6 Ivanovs A, Rybtsov S, Welch L, Anderson RA, Turner ML, Medvinsky A. Highly potent human hematopoietic stem cells first emerge in the intraembryonic aorta- gonad-mesonephros region. J Exp Med 2011; 208:2417–2427. 7 Ivanovs A, Rybtsov S, Anderson RA, Turner ML, Medvinsky A. Identification of the niche and phenotype of the first human hematopoietic stem cells. Stem Cell Rep 2014; 2:449–456. 8 Dzierzak E, Speck NA. Of lineage and legacy: the development of mammalian hematopoietic stem cells. Nat Immunol 2008; 9: 129–136. 9 Medvinsky A, Rybtsov S, Taoudi S. Embryonic origin of the adult hematopoietic system: advances and questions. Development 2011; 138:1017–1031. 10 Till JE, McCulloch EA. A direct measurement of the radiation sensitivity of normal mouse bone marrow cells. Radiat Res 1961; 14:213–222. 11 Becker AJ, McCulloch EA, Till JE. Cytological demonstration of the clonal nature of spleen colonies derived from transplanted mouse marrow cells. Nature 1963; 197: 452–454. 12 Siminovitch L, McCulloch EA, Till JE. The distribution of colony-forming cells among spleen colonies. J Cell Physiol 1963; 62:327–336. 13 Szilvassy SJ, Humphries RK, Lansdorp PM, Eaves AC, Eaves CJ. Quantitative assay for totipotent reconstituting hematopoietic stem cells by a competitive repopu- lation strategy. Proc Natl Acad Sci USA 1990; 87: 8736–8740. 14 Goodell MA, Brose K, Paradis G, Conner AS, Mulligan RC. Isolation and functional properties of murine hematopoietic stem cells that are replicating in vivo. JExp Med 1996; 183: 1797–1806. 15 Hodgson GS, Bradley TR. Properties of haematopoietic stem cells surviving 5-fluorouracil treatment: evidence for a pre-CFU-S cell? Nature 1979; 281:381–382. Figure 4. Future directions and applications of HSC research. (Top 16 Ploemacher RE, van Os R, van Beurden CA, Down JD. Murine haemopoietic stem panel) Ex vivo stem cell expansion. (Bottom panel) Genome editing cells with long-term engraftment and marrow repopulating ability are more of HSCs. resistant to gamma-radiation than are spleen colony forming cells. Int J Radiat Biol 1992; 61:489–499. 17 Spangrude GJ, Heimfeld S, Weissman IL. Purification and characterization of in ways that have revolutionised treatment of blood disorders mouse hematopoietic stem cells. Science 1988; 241:58–62. 18 Okada S, Nakauchi H, Nagayoshi K, Nishikawa S, Nishikawa S, Miura Y et al. and the use of stem cell transplants. Novel outcomes from Enrichment and characterization of murine hematopoietic stem cells that express ongoing stem cell research continue to refine this under- c-kit molecule. Blood 1991; 78: 1706–1712. standing and provides the avenue to continual treatment 19 Morrison SJ, Weissman IL. The long-term repopulating subset of hematopoietic improvements. stem cells is deterministic and isolatable by phenotype. Immunity 1994; 1: Important challenges remain. These include: developing robust 661–673. methods to maintain HSCs in vitro both to enhance research and 20 Morrison SJ, Scadden DT. The bone marrow niche for haematopoietic stem cells. to expand cell numbers for therapy; developing a deeper Nature 2014; 505:327–334. 21 Nombela-Arrieta C, Pivarnik G, Winkel B, Canty KJ, Harley B, Mahoney JE et al. understanding of the HSC niche and intrinsic and extrinsic HSC Quantitative imaging of haematopoietic stem and progenitor cell localization and regulators; and to develop safely the future capacity to hypoxic status in the bone marrow microenvironment. Nat Cell Biol 2013; 15: ‘reprogramme’ cells to HSCs, correct genetically defective HSCs 533–543. that would allow transplantation of ‘corrected’ syngeneic patient 22 Wilson A, Laurenti E, Oser G, van der Wath RC, Blanco-Bose W, Jaworski M et al. cells or transplant reprogrammed haematopoietic cells for Hematopoietic stem cells reversibly switch from dormancy to self-renewal during directed therapy against specific patient diseases (Figure 4). homeostasis and repair. Cell 2008; 135: 1118–1129. Official journal of the Cell Death Differentiation Association Cell Death Discovery (2017) 17002 Haematopoietic stem cells: discovery to the clinic AP Ng and WS Alexander 23 Qian H, Buza-Vidas N, Hyland CD, Jensen CT, Antonchuk J, Mansson R et al. Critical 36 Sawai CM, Babovic S, Upadhaya S, Knapp DJ, Lavin Y, Lau CM et al. Hematopoietic role of thrombopoietin in maintaining adult quiescent hematopoietic stem cells. stem cells are the major source of multilineage hematopoiesis in adult animals. Cell Stem Cell 2007; 1:671–684. Immunity 2016; 45: 597–609. 37 Yang L, Bryder D, Adolfsson J, Nygren J, Mansson R, Sigvardsson M et al. Identi- 24 Yoshihara H, Arai F, Hosokawa K, Hagiwara T, Takubo K, Nakamura Y et al. fication of Lin( − )Sca1(+)kit(+)CD34(+)Flt3 − short-term hematopoietic stem cells Thrombopoietin/MPL signaling regulates hematopoietic stem cell quiescence and capable of rapidly reconstituting and rescuing myeloablated transplant recipients. interaction with the osteoblastic niche. Cell Stem Cell 2007; 1:685–697. Blood 2005; 105: 2717–2723. 25 Zhao M, Perry JM, Marshall H, Venkatraman A, Qian P, He XC et al. Megakaryocytes 38 Benveniste P, Frelin C, Janmohamed S, Barbara M, Herrington R, Hyam D et al. maintain homeostatic quiescence and promote post-injury regeneration of Intermediate-term hematopoietic stem cells with extended but time-limited hematopoietic stem cells. Nat Med 2014; 20: 1321–1326. reconstitution potential. Cell Stem Cell 2010; 6:48–58. 26 Bruns I, Lucas D, Pinho S, Ahmed J, Lambert MP, Kunisaki Y et al. Megakaryocytes 39 Morita Y, Ema H, Nakauchi H. Heterogeneity and hierarchy within the most regulate hematopoietic stem cell quiescence through CXCL4 secretion. Nat Med primitive hematopoietic stem cell compartment. J Exp Med 2010; 207: 1173–1182. 2014; 20: 1315–1320. 40 Oguro H, Ding L, Morrison SJ. SLAM family markers resolve functionally distinct 27 Nakamura-Ishizu A, Takubo K, Kobayashi H, Suzuki-Inoue K, Suda T. CLEC-2 in subpopulations of hematopoietic stem cells and multipotent progenitors. Cell megakaryocytes is critical for maintenance of hematopoietic stem cells in the Stem Cell 2013; 13:102–116. bone marrow. J Exp Med 2015; 212: 2133–2146. 41 Wilson NK, Kent DG, Buettner F, Shehata M, Macaulay IC, Calero-Nieto FJ et al. 28 Baldridge MT, King KY, Boles NC, Weksberg DC, Goodell MA. Quiescent haema- Combined single-cell functional and gene expression analysis resolves hetero- topoietic stem cells are activated by IFN-gamma in response to chronic infection. geneity within stem cell populations. Cell Stem Cell 2015; 16:712–724. Nature 2010; 465:793–797. 42 Larochelle A, Savona M, Wiggins M, Anderson S, Ichwan B, Keyvanfar K et al. 29 Adolfsson J, Mansson R, Buza-Vidas N, Hultquist A, Liuba K, Jensen CT et al. Human and rhesus macaque hematopoietic stem cells cannot be purified based Identification of Flt3+ lympho-myeloid stem cells lacking erythro-megakaryocytic only on SLAM family markers. Blood 2011; 117: 1550–1554. potential a revised road map for adult blood lineage commitment. Cell 2005; 121: 43 Delaney C, Gutman JA, Appelbaum FR. Cord blood transplantation for haema- 295–306. tological malignancies: conditioning regimens, double cord transplant and infectious complications. Br J Haematol 2009; 147: 207–216. 30 Serwold T, Ehrlich LI, Weissman IL. Reductive isolation from bone marrow and 44 Munoz J, Shah N, Rezvani K, Hosing C, Bollard CM, Oran B et al. Concise review: blood implicates common lymphoid progenitors as the major source of thymo- umbilical cord blood transplantation: past, present, and future. Stem Cells Transl poiesis. Blood 2009; 113: 807–815. Med 2014; 3: 1435–1443. 31 Sanjuan-Pla A, Macaulay IC, Jensen CT, Woll PS, Luis TC, Mead A et al. Platelet- 45 Piemontese S, Ciceri F, Labopin M, Bacigalupo A, Huang H, Santarone S et al. biased stem cells reside at the apex of the haematopoietic stem-cell hierarchy. A survey on unmanipulated haploidentical hematopoietic stem cell transplanta- Nature 2013; 502:232–236. tion in adults with acute leukemia. Leukemia 2015; 29:1069–1075. 32 Pietras EM, Reynaud D, Kang YA, Carlin D, Calero-Nieto FJ, Leavitt AD et al. Functionally distinct subsets of lineage-biased multipotent progenitors control blood production in normal and regenerative conditions. Cell Stem Cell 2015; 17: This work is licensed under a Creative Commons Attribution 4.0 35–46. International License. The images or other third party material in this 33 Yamamoto R, Morita Y, Ooehara J, Hamanaka S, Onodera M, Rudolph KL et al. article are included in the article’s Creative Commons license, unless indicated Clonal analysis unveils self-renewing lineage-restricted progenitors generated otherwise in the credit line; if the material is not included under the Creative Commons directly from hematopoietic stem cells. Cell 2013; 154: 1112–1126. license, users will need to obtain permission from the license holder to reproduce the 34 Sun J, Ramos A, Chapman B, Johnnidis JB, Le L, Ho YJ et al. Clonal dynamics of material. To view a copy of this license, visit http://creativecommons.org/licenses/ native haematopoiesis. Nature 2014; 514:322–327. by/4.0/ 35 Schoedel KB, Morcos MN, Zerjatke T, Roeder I, Grinenko T, Voehringer D et al. The bulk of the hematopoietic stem cell population is dispensable for murine steady- state and stress hematopoiesis. Blood 2016; 128: 2285–2296. © The Author(s) 2017 Cell Death Discovery (2017) 17002 Official journal of the Cell Death Differentiation Association http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Cell Death Discovery Springer Journals

Haematopoietic stem cells: past, present and future

Ng, Ashley P; Alexander, Warren S
Cell Death Discovery , Volume 3 (1) – Feb 6, 2017
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Life Sciences; Life Sciences, general; Biochemistry, general; Cell Biology; Stem Cells; Apoptosis; Cell Cycle Analysis
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Citation: Cell Death Discovery (2017) 3, 17002; doi:10.1038/cddiscovery.2017.2 OPEN Official journal of the Cell Death Differentiation Association www.nature.com/cddiscovery REVIEW 1,2 1,2 Ashley P Ng and Warren S Alexander The discovery and characterisation of haematopoietic stem cells has required decades of research. The identification of adult bone marrow as a source of haematopoietic cells capable of protecting an organism from otherwise lethal irradiation led to the intense search for their identity and characteristics. Using functional assays along with evolving techniques for isolation of haematopoietic cells, haematopoietic stem cell populations were able to be enriched and their characteristics analysed. The key haematopoietic stem cell characteristics of pluripotentiality and the ability for self-renewal have emerged as characteristics of several haematopoietic stem cell populations, including those that have recently challenged the conventional concepts of the haematopoietic hierarchy. Human allogeneic stem cell therapy relies on these functional characteristics of haematopoietic stem cells that can be isolated from peripheral blood, bone marrow or cord blood, with the additional requirement that immunological barriers need to be overcome to allow sustained engraftment while minimising risk of graft-versus-host disease developing in the recipient of transplanted stem cells. Current and future research will continue to focus on the identification of haematopoietic stem cell regulators and methods for in vitro and in vivo stem cell manipulation, including genome editing, to expand the scope, potential and safety of therapy using haematopoietic stem cells. Cell Death Discovery (2017) 3, 17002; doi:10.1038/cddiscovery.2017.2; published online 6 February 2017 KEY-POINTS Definitive haematopoiesis in the embryo begins with the emergence of the first identifiable HSC in the aorto-gonado- 6,7 mesonephros region. Thereafter, haematopoiesis shifts to the Haematopoietic stem cells are rare cells with characteristics of fetal liver, and subsequently to the bone marrow, where HSCs will pluripotency and self-renewal that are capable of generating an 8,9 reside for the life of the mammalian organism (Figure 1). entire haematopoeitic system. Haematopoietic stem cells have been identified at defined stages of embryonic development and several subsets have IDENTIFICATION OF HSCS been characterised in adult haematopoiesis. The relative contribution of haematopoietic stem cells to steady- It became apparent, initially through work that sought to state and stress haematopoiesis remains controversial. characterise radiation sensitivity, that donor adult bone marrow Allogeneic haematopoietic stem cell transplantation therapy transplanted into syngeneic irradiated murine recipients was in human requires significant immunological barriers to be capable of protecting the recipients from lethal irradiation by overcome. regenerating (reconstituting) the irradiation-ablated haematopoie- Current and future research aims to identify key stem cell tic system. This research was crucial in the development of the concept of HSC as cells in the bone marrow capable of generating regulators and methods for in vitro and in vivo stem cell manipulation including genome editing. the complete blood cell system, although at this time the specific cell had yet to be isolated and characterised. In these early experiments, donor-derived clonogenic colonies Haematopoietic stem cells (HSC) are the architects of definitive of multiple haematopoietic lineages were able to be macro- haematopoiesis, that is, blood cell production that occurs 10,11 scopically identified in the spleen of transplanted recipients. continuously during the life of an organism. Each HSC is These spleen colony-forming units, although not definitive HSCs, programmed to allow efficient production of the cellular blood were nevertheless useful in allowing characterisation of progenitor components with a manifest purpose that has been shaped by cells responsible for haematopoietic reconstitution. Specific evolution: from red cells that allow efficient carriage of oxygen, progenitor cells appeared to possess the ability to form multiple megakaryocytes and their platelet progeny that interact with haematopoietic lineages from within the one colony (multi- blood vessels and soluble coagulation factors to regulate clotting, potency), while others appeared able to form daughter cells that to the cells of the innate and acquired immune system that act retained the characteristics of the original parental cell (self- against microbial attack. HSCs are defined by their pluripotenti- renewal). These two important characteristics ultimately came to ality, the capacity for a single HSC to generate any and all of the diverse mature functional haematopoietic cell types. Key genes be recognised as definitive characteristics of HSC. and select genetic programmes are invoked for the maintenance, The identification and characterisation of HSCs ultimately required strategies to separate these rare bone marrow cells from or self-renewal of HSCs and for the formation of the specific 1–5 haematopoietic lineages. more numerous cellular components. Functional competitive 1 2 The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, VIC, Australia and Department of Medical Biology, The University of Melbourne, Parkville, VIC, Australia. Correspondence: AP Ng ([email protected]) Received 21 December 2016; accepted 29 December 2016; Edited by A Rufini Haematopoietic stem cells: discovery to the clinic AP Ng and WS Alexander Figure 2. Immunophenotypic markers of adult murine HSCs and Figure 1. The journey from fetal to adult haematopoiesis adapted ‘lineage-restricted’ HSC populations. See references in main text. from Dzierzak and Speck. AGM, aorto-gonado-mesonephros; PsP, para-aortic-splanchnopleura. See references in main text. state. However, other studies have yielded apparently conflicting results on the relative contribution of HSCs to steady state and 35,36 repopulating unit assays estimated the frequency of these rare stress haematopoiesis, a current controversy that remains to cells as one in 10 000 cells in bone marrow. Like the proverbial be resolved. search for the needle in a haystack, HSCs were eventually In the setting of bone marrow transplantation, which is isolated with increasing purity based on physical properties, such dependent on HSCs to sustainably reconstitute haematopoiesis, as Hoescht 33342 supravital dye exclusion, resistance to further refinement of cell surface markers have also identified 15 16 5-fluorouracil or γ-irradiation. Ultimately, however, it was the specific subsets of HSCs with more limited capacity for self- application of flow cytometry and the use of specific cell surface renewal, yet important for maintaining haematopoiesis in the 37,38 antigen markers that led to the ability to prospectively identify short and intermediate terms after transplantation. Stem cells cell populations able to reconstitute multiple lineages upon capable of true long-term reconstitution with durable self-renewal transplantation, and capable of self-renewal as judged by serial potential do appear to be a very rare but essential cell popu- 39–41 transplantation assays. These cell populations, enriched for HSCs, lation required for long-term haematopoietic engraftment were notable for their lack of mature lineage antigen expression, (Figure 2). and expression of antigens such as cKit, the cellular receptor for 18,19 the cytokine stem cell factor. HSCs were found to possess unique properties that set them BONE MARROW TRANSPLANTATION AS THERAPY apart from other blood-forming progenitor cells. In addition to the Although murine haematopoiesis reflects human haematopoiesis properties of pluripotency and self-renewal, adult long-term HSCs in many ways, the immunophenotypic markers of human HSCs − + − were found to reside in a specific niche environment in the bone (Lineage CD34 CD38 ) differ from functionally similar murine marrow, which was closely associated with endosteum, and counterparts. Unlike inbred genetically and immunologically where they exist in conditions of relative hypoxia. Here, HSC identical mouse strains, successful allogeneic transplantation exists predominantly in a non-replicative and quiescent state, in therapy in humans requires significant immunological barriers to 23,24 which signalling by the cytokine thrombopoietin and the be overcome. The discovery of the HLA system of MHC class I and presence of megakaryocytes are recognised to have an important II receptors, which engage T-cell antigen receptors, allows 25–27 role. In contexts that place the haematopoietic system under histocompatible matching of donors and recipients. This is stress, such as chronic infection, these quiescent stem cells are supplemented with the use of immunosuppression during and recruited into cell cycle, for example, via interferon signalling, after the transplantation of allogeneic stem cells from volunteer- which is associated with a numerical increase in downstream related and -unrelated donors. Advancement of stem cell progenitor cells. Evidence increasingly suggests that lineage transplantation therapy has focussed on research to broaden specification can occur very early in the haematopoietic hierarchy the availability of donors to patients. Use of cord blood units as a 29–32 43,44 in immunophenotypically defined ‘stem cell’ populations source of stem cells and recently developed conditioning and (Figure 2), supporting findings that self-renewing lineage- immunosuppressive regimens have allowed haploidentical restricted progenitors may emerge directly from HSC. A transplantation to become a therapeutic reality while limiting significant degree of complexity may therefore exist in the the immunological consequence of graft-versus-host disease. pathways via which mature haematopoietic lineages develop from These approaches are increasingly making the option of HSC and progenitor populations. More direct pathways from HSC allogeneic transplantation available to patients who otherwise to specific mature cells may coexist alongside traditional models do not have a matched-related or volunteer-unrelated donor of progenitor population hierarchies. Recent evidence from clonal source of stem cells (Figure 3). dynamic studies tracing the origin of blood cells over time has suggested that steady-state blood cell maintenance does not THE FUTURE incessantly call upon the quiescent HSCs to enter into cell cycle, but rather, successive recruitment of long-lived progenitor Research defining the nature and regulation of HSCs has populations appears to primarily maintain blood cells at steady allowed regulators of blood cell production to be manipulated Cell Death Discovery (2017) 17002 Official journal of the Cell Death Differentiation Association Haematopoietic stem cells: discovery to the clinic AP Ng and WS Alexander ACKNOWLEDGEMENTS An earlier version of this manuscript was published in Australian Biochemist (Vol. 47, No. 1, April 2016). This work was supported by the Australian National Health and Medical Research Council Project Grant (1060179; to APN), Program Grant (1016647), Fellowships (1058344; to WSA), Independent Research Institutes Infrastructure Support Scheme Grant (9000220) and a Victorian State Government Operational Infrastructure Support Grant. COMPETING INTERESTS The authors declare no conflict of interest. REFERENCES 1 Ivanova NB, Dimos JT, Schaniel C, Hackney JA, Moore KA, Lemischka IR. A stem cell molecular signature. Science 2002; 298: 601–604. 2 Mercer EM, Lin YC, Murre C. Factors and networks that underpin early hemato- poiesis. Semin Immunol 2011; 23:317–325. 3 Novershtern N, Subramanian A, Lawton LN, Mak RH, Haining WN, McConkey ME et al. Densely interconnected transcriptional circuits control cell states in human hematopoiesis. Cell 2011; 144:296–309. Figure 3. Human HSC transplantation therapy. HLA-matched adult, 4 Moignard V, Macaulay IC, Swiers G, Buettner F, Schütte J, Calero-Nieto FJ et al. cord blood or haploidentical adult donor stem and progenitor cells Characterization of transcriptional networks in blood stem and progenitor cells are transplanted intravenously into a recipient following condition- using high-throughput single-cell gene expression analysis. Nat Cell Biol 2013; 15: ing therapy to permit engraftment of donor marrow into the 363–372. recipient. Immune suppression is administered to prevent acute 5 Riddell J, Gazit R, Garrison BS, Guo G, Saadatpour A, Mandal PK et al. Repro- graft-versus-host disease. gramming committed murine blood cells to induced hematopoietic stem cells with defined factors. Cell 2014; 157:549–564. 6 Ivanovs A, Rybtsov S, Welch L, Anderson RA, Turner ML, Medvinsky A. Highly potent human hematopoietic stem cells first emerge in the intraembryonic aorta- gonad-mesonephros region. 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The images or other third party material in this 33 Yamamoto R, Morita Y, Ooehara J, Hamanaka S, Onodera M, Rudolph KL et al. article are included in the article’s Creative Commons license, unless indicated Clonal analysis unveils self-renewing lineage-restricted progenitors generated otherwise in the credit line; if the material is not included under the Creative Commons directly from hematopoietic stem cells. Cell 2013; 154: 1112–1126. license, users will need to obtain permission from the license holder to reproduce the 34 Sun J, Ramos A, Chapman B, Johnnidis JB, Le L, Ho YJ et al. Clonal dynamics of material. To view a copy of this license, visit http://creativecommons.org/licenses/ native haematopoiesis. Nature 2014; 514:322–327. by/4.0/ 35 Schoedel KB, Morcos MN, Zerjatke T, Roeder I, Grinenko T, Voehringer D et al. The bulk of the hematopoietic stem cell population is dispensable for murine steady- state and stress hematopoiesis. 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