New paradigms on hematopoietic stem cell differentiation

Abstract

Ever since hematopoietic stem cells (HSCs) were first identified half a century ago, their differentiation roadmap has been extensively studied. The classical model of hematopoiesis has long held as a dogma that HSCs reside at the top of a hierarchy in which HSCs possess self-renewal capacity and can progressively give rise to all blood lineage cells. However, over the past several years, with advances in single cell technologies, this developmental scheme has been challenged. In this review, we discuss the evidence supporting heterogeneity within HSC and progenitor populations as well as the hierarchical models revised by novel approaches mainly in mouse system. These evolving views provide further understanding of hematopoiesis and highlight the complexity of hematopoietic differentiation.

Key words： hematopoietic stem cell; hierarchy; heterogeneity; differentiation

References

1 Adolfsson J, Mansson R, Buza-Vidas N, Hultquist A, Liuba K, Jensen CT, Bryder D, Yang L, Borge OJ, Thoren LA (2005) Identification of Flt3+ lympho-myeloid stem cells lacking erythromegakaryocytic potential a revised road map for adult blood lineage commitment. Cell 121:295–306

2 Akashi K, Traver D, Miyamoto T, Weissman IL (2000) A clonogenic common myeloid progenitor that gives rise to all myeloid lineages. Nature 404:193–197

3 Belyaev NN, Brown DE, Diaz AI, Rae A, Jarra W, Thompson J, Langhorne J, Potocnik AJ (2010) Induction of an IL7-R(+)c-Kit(hi) myelolymphoid progenitor critically dependent on IFN-gamma signaling during acute malaria. Nat Immunol 11:477–485

4 Benveniste P, Frelin C, Janmohamed S, Barbara M, Herrington R, Hyam D, Iscove NN (2010) Intermediate-term hematopoietic stem cells with extended but time-limited reconstitution potential. Cell Stem Cell 6:48–58

5 Benz C, Copley MR, Kent DG, Wohrer S, Cortes A, Aghaeepour N, Ma E, Mader H, Rowe K, Day C(2012) Hematopoietic stem cell subtypes expand differentially during development and display distinct lymphopoietic programs. Cell Stem Cell 10:273–283

6 Boyer SW, Schroeder AV, Smith-Berdan S, Forsberg EC (2011) All hematopoietic cells develop from hematopoietic stem cells through Flk2/Flt3-positive progenitor cells. Cell Stem Cell 9:64–73

7 Bruns I, Lucas D, Pinho S, Ahmed J, Lambert MP, Kunisaki Y, Scheiermann C, Schiff L, Poncz M, Bergman A (2014) Megakaryocytes regulate hematopoietic stem cell quiescence through CXCL4 secretion. Nat Med 20(11):1315

8 Buenrostro JD, Corces MR, Lareau CA, Wu B, Schep AN, Aryee MJ, Majeti R, Chang HY, Greenleaf WJ (2018) Integrated single-cell analysis maps the continuous regulatory landscape of human hematopoietic differentiation. Cell 173:1535–1548 e1516

9 Busch K, Klapproth K, Barile M, Flossdorf M, Holland-Letz T, Schlenner SM, Reth M, Hofer T, Rodewald HR (2015) Fundamental properties of unperturbed haematopoiesis from stem cells in vivo. Nature 518:542–546

10 Cao J, Cusanovich DA, Ramani V, Aghamirzaie D, Pliner HA, Hill AJ, Daza RM, McFaline-Figueroa JL, Packer JS, Christiansen L (2018) Joint profiling of chromatin accessibility and gene expression in thousands of single cells. Science 361:1380–1385

11 Carrelha J, Meng Y, Kettyle LM, Luis TC, Norfo R, Alcolea V, Boukarabila H, Grasso F, Gambardella A, Grover A (2018) Hierarchically related lineage-restricted fates of multipotent haematopoietic stem cells. Nature 554:106–111

12 Crane GM, Jeffery E, Morrison SJ (2017) Adult haematopoietic stem cell niches. Nat Rev Immunol 17:573–590

13 Cusanovich DA, Hill AJ, Aghamirzaie D, Daza RM, Pliner HA, Berletch JB, Filippova GN, Huang X, Christiansen L, DeWitt WS(2018) A single-cell atlas of in vivo mammalian chromatin accessibility. Cell 174:1309–1324 e1318

14 Dick JE (2003) Stem cells: Self-renewal writ in blood. Nature 423:231–233

15 Dykstra B, Kent D, Bowie M, McCaffrey L, Hamilton M, Lyons K, Lee SJ, Brinkman R, Eaves C (2007) Long-term propagation of distinct hematopoietic differentiation programs in vivo. Cell Stem Cell 1:218–229

16 Eng CL, Lawson M, Zhu Q, Dries R, Koulena N, Takei Y, Yun J, Cronin C, Karp C, Yuan GC (2019) Transcriptome-scale super-resolved imaging in tissues by RNA seqFISH. Nature 568(7751):235–239

17 Evrard M, Kwok IWH, Chong SZ, Teng KWW, Becht E, Chen J, Sieow JL, Penny HL, Ching GC, Devi S (2018) Developmental analysis of bone marrow neutrophils reveals populations specialized in expansion, trafficking, and effector functions. Immunity 48:364–379 e368

18 Forsberg EC, Serwold T, Kogan S, Weissman IL, Passegue E (2006) New evidence supporting megakaryocyte-erythrocyte potential of flk2/flt3+ multipotent hematopoietic progenitors. Cell 126:415–426

19 Haas S, Hansson J, Klimmeck D, Loeffler D, Velten L, Uckelmann H, Wurzer S, Prendergast AM, Schnell A, Hexel K (2015) Inflammation-induced emergency megakaryopoiesis driven by hematopoietic stem cell-like megakaryocyte progenitors. Cell Stem Cell 17(4):422–434

20 Huang H, Cantor AB (2009) Common features of megakaryocytes and hematopoietic stem cells: what’s the connection? J Cell Biochem 107:857–864

21 Ikuta K, Weissman IL (1992) Evidence that hematopoietic stem cells express mouse c-kit but do not depend on steel factor for their generation. Proc Natl Acad Sci USA 89:1502–1506

22 Itkin T, Gur-Cohen S, Spencer JA, Schajnovitz A, Ramasamy SK, Kusumbe AP, Ledergor G, Jung Y, Milo I, Poulos MG (2016) Distinct bone marrow blood vessels differentially regulate haematopoiesis. Nature 532:323–328

23 Jacobsen SEW, Nerlov C (2019) Haematopoiesis in the era of advanced single-cell technologies. Nat Cell Biol 21:2–8

24 Karamitros D, Stoilova B, Aboukhalil Z, Hamey F, Reinisch A, Samitsch M, Quek L, Otto G, Repapi E, Doondeea J (2018) Single-cell analysis reveals the continuum of human lymphomyeloid progenitor cells. Nat Immunol 19:85–97

25 Kiel MJ, Yilmaz OH, Iwashita T, Terhorst C, Morrison SJ (2005) SLAM family receptors distinguish hematopoietic stem and progenitor cells and reveal endothelial niches for stem cells. Cell 121:1109–1121

26 Kim MH, Yang D, Kim M, Kim SY, Kim D, Kang SJ (2017) A latelineage murine neutrophil precursor population exhibits dynamic changes during demand-adapted granulopoiesis. Sci Rep 7:39804

27 Kondo M, Weissman IL, Akashi K (1997) Identification of clonogenic common lymphoid progenitors in mouse bone marrow. Cell 91:661–672

28 Laurenti E, Gottgens B (2018) From haematopoietic stem cells to complex differentiation landscapes. Nature 553:418–426

29 Lu R, Czechowicz A, Seita J, Jiang D, Weissman IL (2019) Clonallevel lineage commitment pathways of hematopoietic stem cells in vivo. Proc Natl Acad Sci USA 116:1447–1456

30 Lu R, Neff NF, Quake SR, Weissman IL (2011) Tracking single hematopoietic stem cells in vivo using high-throughput sequencing in conjunction with viral genetic barcoding. Nat Biotechnol 29:928–933

31 Macaulay IC, Svensson V, Labalette C, Ferreira L, Hamey F, Voet T, Teichmann SA, Cvejic A (2016) Single-cell RNA-sequencing reveals a continuous spectrum of differentiation in hematopoietic cells. Cell Rep 14:966–977

32 Mantel CR, O’Leary HA, Chitteti BR, Huang X, Cooper S, Hangoc G, Brustovetsky N, Srour EF, Lee MR, Messina-Graham S (2015) Enhancing hematopoietic stem cell transplantation efficacy by mitigating oxygen shock. Cell 161:1553–1565

33 Manz MG, Miyamoto T, Akashi K, Weissman IL (2002) Prospective isolation of human clonogenic common myeloid progenitors. Proc Natl Acad Sci USA 99:11872–11877

34 Mendelson A, Frenette PS (2014) Hematopoietic stem cell niche maintenance during homeostasis and regeneration. Nat Med 20:833–846

35 Metcalf D (2008) Hematopoietic cytokines. Blood 111:485–491

36 Moignard V, Macaulay IC, Swiers G, Buettner F, Schutte J, Calero-Nieto FJ, Kinston S, Joshi A, Hannah R, Theis FJ (2013) Characterization of transcriptional networks in blood stem and progenitor cells using high-throughput single-cell gene expression analysis. Nat Cell Biol 15:363–372

37 Morita Y, Ema H, Nakauchi H (2010) Heterogeneity and hierarchy within the most primitive hematopoietic stem cell compartment. J Exp Med 207(6):1173–1182

38 Morrison SJ, Scadden DT (2014) The bone marrow niche for haematopoietic stem cells. Nature 505:327–334

39 Morrison SJ, Uchida N, Weissman IL (1995) The biology of hematopoietic stem cells. Annu Rev Cell Dev Biol 11:35–71

40 Morrison SJ, Wandycz AM, Hemmati HD, Wright DE, Weissman IL (1997) Identification of a lineage of multipotent hematopoietic progenitors. Development 124:1929–1939

41 Muller-Sieburg CE, Cho RH, Karlsson L, Huang JF, Sieburg HB (2004) Myeloid-biased hematopoietic stem cells have extensive self-renewal capacity but generate diminished lymphoid progeny with impaired IL-7 responsiveness. Blood 103:4111–4118

42 Muller-Sieburg CE, Cho RH, Thoman M, Adkins B, Sieburg HB (2002) Deterministic regulation of hematopoietic stem cell selfrenewal and differentiation. Blood 100:1302–1309

43 Nagano T, Lubling Y, Stevens TJ, Schoenfelder S, Yaffe E, Dean W, Laue ED, Tanay A, Fraser P (2013) Single-cell Hi-C reveals cellto-cell variability in chromosome structure. Nature 502:59–64

44 Nakorn TN, Miyamoto T, Weissman IL (2003) Characterization of mouse clonogenic megakaryocyte progenitors. Proc Natl Acad Sci USA 100:205–210

45 Nestorowa S, Hamey FK, Pijuan Sala B, Diamanti E, Shepherd M, Laurenti E, Wilson NK, Kent DG, Gottgens B (2016) A single-cell resolution map of mouse hematopoietic stem and progenitor cell differentiation. Blood 128:e20–31

46 Nombela-Arrieta C, Pivarnik G, Winkel B, Canty KJ, Harley B, Mahoney JE, Park SY, Lu J, Protopopov A, Silberstein LE (2013) Quantitative imaging of haematopoietic stem and progenitor cell localization and hypoxic status in the bone marrow microenvironment. Nat Cell Biol 15:533–543

47 Notta F, Zandi S, Takayama N, Dobson S, Gan OI, Wilson G, Kaufmann KB, McLeod J, Laurenti E, Dunant CF (2016) Distinct routes of lineage development reshape the human blood hierarchy across ontogeny. Science 351:aab2116

48 Oguro H, Ding L, Morrison SJ (2013) SLAM family markers resolve functionally distinct subpopulations of hematopoietic stem cells and multipotent progenitors. Cell Stem Cell 13:102–116

49 Okada S, Nakauchi H, Nagayoshi K, Nishikawa S, Miura Y, Suda T (1992) In vivo and in vitro stem cell function of c-kit- and Sca-1-positive murine hematopoietic cells. Blood 80:3044–3050

50 Orkin SH (2000) Diversification of haematopoietic stem cells to specific lineages. Nat Rev Genet 1:57–64

51 Osawa M, Hanada K, Hamada H, Nakauchi H (1996) Long-term lymphohematopoietic reconstitution by a single CD34-low/negative hematopoietic stem cell. Science 273:242–245

52 Paul F, Arkin Y, Giladi A, Jaitin DA, Kenigsberg E, Keren-Shaul H, Winter D, Lara-Astiaso D, Gury M, Weiner A (2015) Transcriptional heterogeneity and lineage commitment in myeloid progenitors. Cell 163:1663–1677

53 Pei W, Feyerabend TB, Rossler J, Wang X, Postrach D, Busch K, Rode I, Klapproth K, Dietlein N, Quedenau C (2017) Polylox barcoding reveals haematopoietic stem cell fates realized in vivo. Nature 548:456–460

54 Pietras EM, Reynaud D, Kang YA, Carlin D, Calero-Nieto FJ, Leavitt AD, Stuart JM, Gottgens B, Passegue E (2015) Functionally distinct subsets of lineage-biased multipotent progenitors control blood production in normal and regenerative conditions. Cell Stem Cell 17:35–46

55 Pinho S, Marchand T, Yang E, Wei Q, Nerlov C, Frenette PS (2018) Lineage-biased hematopoietic stem cells are regulated by distinct niches. Dev Cell 44:634–641 e634

56 Pronk CJ, Rossi DJ, Mansson R, Attema JL, Norddahl GL, Chan CK, Sigvardsson M, Weissman IL, Bryder D (2007) Elucidation of the phenotypic, functional, and molecular topography of a myeloerythroid progenitor cell hierarchy. Cell Stem Cell 1:428–442

57 Reya T (2003) Regulation of hematopoietic stem cell self-renewal. Recent Progr Horm Res 58:283–295

58 Reya T, Morrison SJ, Clarke MF, Weissman IL (2001) Stem cells, cancer, and cancer stem cells. Nature 414:105–111

59 Robb L (2007) Cytokine receptors and hematopoietic differentiation. Oncogene 26:6715–6723

60 Rodriguez-Fraticelli AE, Wolock SL, Weinreb CS, Panero R, Patel SH, Jankovic M, Sun J, Calogero RA, Klein AM, Camargo FD (2018) Clonal analysis of lineage fate in native haematopoiesis. Nature 553:212–216

61 Rodriques SG, Stickels RR, Goeva A, Martin CA, Murray E, Vanderburg CR, Welch J, Chen LM, Chen F, Macosko EZ (2019) Slide-seq: A scalable technology for measuring genomewide expression at high spatial resolution. Science 363:1463–1467

62 Sanjuan-Pla A, Macaulay IC, Jensen CT, Woll PS, Luis TC, Mead A, Moore S, Carella C, Matsuoka S, Jones TB (2013) Plateletbiased stem cells reside at the apex of the haematopoietic stemcell hierarchy. Nature 502(7470):232

63 Satpathy AT, Saligrama N, Buenrostro JD, Wei Y, Wu B, Rubin AJ, Granja JM, Lareau CA, Li R, Qi Y (2018) Transcript-indexed ATAC-seq for precision immune profiling. Nat Med 24:580–590

64 Sawai CM, Babovic S, Upadhaya S, Knapp D, Lavin Y, Lau CM, Goloborodko A, Feng J, Fujisaki J, Ding L (2016) Hematopoietic stem cells are the major source of multilineage hematopoiesis in adult animals. Immunity 45:597–609

65 Seita J, Weissman IL (2010) Hematopoietic stem cell: self-renewal versus differentiation. Wiley Interdiscip Rev Syst Biol Med 2:640–653

66 Shin JY, Hu W, Naramura M, Park CY (2014) High c-Kit expression identifies hematopoietic stem cells with impaired self-renewal and megakaryocytic bias. J Exp Med 211:217–231

67 Spangrude GJ, Heimfeld S, Weissman IL (1988) Purification and characterization of mouse hematopoietic stem cells. Science 241:58–62

68 Spencer JA, Ferraro F, Roussakis E, Klein A, Wu J, Runnels JM, Zaher W, Mortensen LJ, Alt C, Turcotte R (2014) Direct measurement of local oxygen concentration in the bone marrow of live animals. Nature 508:269–273

69 Suda T, Takubo K, Semenza GL (2011) Metabolic regulation of hematopoietic stem cells in the hypoxic niche. Cell Stem Cell 9:298–310

70 Sugiyama T, Kohara H, Noda M, Nagasawa T (2006) Maintenance of the hematopoietic stem cell pool by CXCL12-CXCR49 chemokine signaling in bone marrow stromal cell niches. Immunity 25:977–988

71 Sun J, Ramos A, Chapman B, Johnnidis JB, Le L, Ho YJ, Klein A, Hofmann O, Camargo FD (2014) Clonal dynamics of native haematopoiesis. Nature 514:322–327

72 Till JE, Mc CE (1961) A direct measurement of the radiation sensitivity of normal mouse bone marrow cells. Radiat Res 14:213–222

73 Velten L, Haas SF, Raffel S, Blaszkiewicz S, Islam S, Hennig BP, Hirche C, Lutz C, Buss EC, Nowak D (2017) Human haematopoietic stem cell lineage commitment is a continuous process. Nat Cell Biol 19:271–281

74 Wang JF, Liu ZY, Groopman JE (1998) The alpha-chemokine receptor CXCR74 is expressed on the megakaryocytic lineage from progenitor to platelets and modulates migration and adhesion. Blood 92:756–764

75 Wang X, Allen WE, Wright MA, Sylwestrak EL, Samusik N, Vesuna S, Evans K, Liu C, Ramakrishnan C, Liu J (2018) Threedimensional intact-tissue sequencing of single-cell transcriptional states. Science 361(6400):eaat5691

76 Wilson A, Laurenti E, Oser G, van der Wath RC, Blanco-Bose W, Jaworski M, Offner S, Dunant CF, Eshkind L, Bockamp E (2008) Hematopoietic stem cells reversibly switch from dormancy to self-renewal during homeostasis and repair. Cell 135:1118–1129

77 Wilson NK, Kent DG, Buettner F, Shehata M, Macaulay IC, Calero-Nieto FJ, Sanchez Castillo MOedekoven CA, Diamanti E, Schulte R (2015) Combined single-cell functional and gene expression analysis resolves heterogeneity within stem cell populations. Cell Stem Cell 16:712–724

78 Yamamoto R, Morita Y, Ooehara J, Hamanaka S, Onodera M, Rudolph KL, Ema H, Nakauchi H (2013) Clonal analysis unveils self-renewing lineage-restricted progenitors generated directly from hematopoietic stem cells. Cell 154:1112–1126

79 Yang L, Bryder D, Adolfsson J, Nygren J, Mansson R, Sigvardsson M, Jacobsen SE (2005) Identification of Lin(-)Sca1(+)kit(+)CD34 (+)Flt3- short-term hematopoietic stem cells capable of rapidly reconstituting and rescuing myeloablated transplant recipients. Blood 105:2717–2723

80 Yoshihara H, Arai F, Hosokawa K, Hagiwara T, Takubo K, Nakamura Y, Gomei Y, Iwasaki H, Matsuoka S, Miyamoto K (2007) Thrombopoietin/MPL signaling regulates hematopoietic stem cell quiescence and interaction with the osteoblastic niche. Cell Stem Cell 1:685–697

81 Zhang CC, Lodish HF (2008) Cytokines regulating hematopoietic stem cell function. Curr Opin Hematol 15:307–

82 Zhao M, Perry JM, Marshall H, Venkatraman A, Qian P, He XC, Ahamed J, Li L (2014) Megakaryocytes maintain homeostatic quiescence and promote post-injury regeneration of hematopoietic stem cells. Nat Med 20(11):1321

83 Zhu J, Emerson SG (2002) Hematopoietic cytokines, transcription factors and lineage commitment. Oncogene 21:3295–3313

84 Zhu YP, Padgett L, Dinh HQ, Marcovecchio P, Blatchley A, Wu R, Ehinger E, Kim C, Mikulski Z, Seumois G (2018) Identification of an early unipotent neutrophil progenitor with pro-tumoral activity in mouse and human bone marrow. Cell Rep 24:2329–2341 e2328