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Tuning of the Hematopoietic Stem Cell Compartment in its Inflammatory Environment

  • Cancer and Stem Cells (D Starczynowski and G Huang, Section Editors)
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Abstract

Purpose of Review

The hematopoietic stem cell (HSC) compartment is the cornerstone of a lifelong blood cell production but also contributes to the ability of the hematopoietic system to dynamically respond to environmental challenges. This review summarizes our knowledge about the interaction between HSCs and its inflammatory environment during life and questions how its disruption could affect the health of the hematopoietic system.

Recent Findings

The latest research demonstrates the direct role of inflammatory signals in promoting the emergence of the HSCs during development and in setting their steady-state activity in adults. They indicate that inflammatory patho-physiological conditions or immunological history could shape the structure and biology of the HSC compartment, therefore altering its overall fitness.

Summary

Through instructive and/or selective mechanisms, the inflammatory environment seems to provide a key homeostatic signal for HSCs. Although the mechanistic basis of this complex interplay remains to be fully understood, its dysregulation has broad consequences on HSC physiology and the development of hematological diseases. As such, developing experimental models that fully recapitulate a normal basal inflammatory state could be essential to fully assess HSC biology in native conditions.

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References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major Importance

  1. Medzhitov R. Origin and physiological roles of inflammation. Nature. 2008;454(7203):428–35. https://doi.org/10.1038/nature07201.

    Article  PubMed  CAS  Google Scholar 

  2. Kauts ML, Vink CS, Dzierzak E. Hematopoietic (stem) cell development—how divergent are the roads taken? FEBS Lett. 2016;590(22):3975–86. https://doi.org/10.1002/1873-3468.12372.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  3. Clements WK, Traver D. Signalling pathways that control vertebrate haematopoietic stem cell specification. Nat Rev Immunol. 2013;13(5):336–48. https://doi.org/10.1038/nri3443.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  4. • Espin-Palazon R, Weijts B, Mulero V, Traver D. Proinflammatory signals as fuel for the fire of hematopoietic stem cell emergence. Trends Cell Biol. 2018;28(1):58–66. https://doi.org/10.1016/j.tcb.2017.08.003. Detailed review of the inflammatory mechanisms contributing to HSC emergence in the embryo.

    Article  PubMed  CAS  Google Scholar 

  5. Espin-Palazon R, Stachura DL, Campbell CA, Garcia-Moreno D, Del Cid N, Kim AD, et al. Proinflammatory signaling regulates hematopoietic stem cell emergence. Cell. 2014;159(5):1070–85. https://doi.org/10.1016/j.cell.2014.10.031.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  6. He Q, Zhang C, Wang L, Zhang P, Ma D, Lv J, et al. Inflammatory signaling regulates hematopoietic stem and progenitor cell emergence in vertebrates. Blood. 2015;125(7):1098–106. https://doi.org/10.1182/blood-2014-09-601542.

    Article  PubMed  CAS  Google Scholar 

  7. Li Y, Esain V, Teng L, Xu J, Kwan W, Frost IM, et al. Inflammatory signaling regulates embryonic hematopoietic stem and progenitor cell production. Genes Dev. 2014;28(23):2597–612. https://doi.org/10.1101/gad.253302.114.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  8. Sawamiphak S, Kontarakis Z, Stainier DY. Interferon gamma signaling positively regulates hematopoietic stem cell emergence. Dev Cell. 2014;31(5):640–53. https://doi.org/10.1016/j.devcel.2014.11.007.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  9. Funkhouser LJ, Bordenstein SR. Mom knows best: the universality of maternal microbial transmission. PLoS Biol. 2013;11(8):e1001631. https://doi.org/10.1371/journal.pbio.1001631.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  10. Basha S, Surendran N, Pichichero M. Immune responses in neonates. Expert Rev Clin Immunol. 2014;10(9):1171–84. https://doi.org/10.1586/1744666x.2014.942288.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  11. Copley MR, Eaves CJ. Developmental changes in hematopoietic stem cell properties. Exp Mol Med. 2013;45:e55. https://doi.org/10.1038/emm.2013.98.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  12. Beaudin AE, Boyer SW, Perez-Cunningham J, Hernandez GE, Derderian SC, Jujjavarapu C, et al. A transient developmental hematopoietic stem cell gives rise to innate-like B and T cells. Cell Stem Cell. 2016;19(6):768–83. https://doi.org/10.1016/j.stem.2016.08.013.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  13. Bowie MB, McKnight KD, Kent DG, McCaffrey L, Hoodless PA, Eaves CJ. Hematopoietic stem cells proliferate until after birth and show a reversible phase-specific engraftment defect. J Clin Invest. 2006;116(10):2808–16. https://doi.org/10.1172/jci28310.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  14. Bashan A, Gibson TE, Friedman J, Carey VJ, Weiss ST, Hohmann EL, et al. Universality of human microbial dynamics. Nature. 2016;534(7606):259–62. https://doi.org/10.1038/nature18301.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  15. Turnbaugh PJ, Ley RE, Hamady M, Fraser-Liggett CM, Knight R, Gordon JI. The human microbiome project. Nature. 2007;449(7164):804–10. https://doi.org/10.1038/nature06244.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  16. •• Kundu P, Blacher E, Elinav E, Pettersson S. Our gut microbiome: the evolving inner self. Cell. 2017;171(7):1481–93. https://doi.org/10.1016/j.cell.2017.11.024. Comprehensive review of the evolving relationship of the gut microbiota with its host across human lifespan.

    Article  PubMed  CAS  Google Scholar 

  17. Chow J, Lee SM, Shen Y, Khosravi A, Mazmanian SK. Host-bacterial symbiosis in health and disease. Adv Immunol. 2010;107:243–74. https://doi.org/10.1016/b978-0-12-381300-8.00008-3.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  18. Manzo VE, Bhatt AS. The human microbiome in hematopoiesis and hematologic disorders. Blood. 2015;126(3):311–8. https://doi.org/10.1182/blood-2015-04-574392.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  19. Smith K, McCoy KD, Macpherson AJ. Use of axenic animals in studying the adaptation of mammals to their commensal intestinal microbiota. Semin Immunol. 2007;19(2):59–69. https://doi.org/10.1016/j.smim.2006.10.002.

    Article  PubMed  CAS  Google Scholar 

  20. Khosravi A, Yanez A, Price JG, Chow A, Merad M, Goodridge HS, et al. Gut microbiota promote hematopoiesis to control bacterial infection. Cell Host Microbe. 2014;15(3):374–81. https://doi.org/10.1016/j.chom.2014.02.006.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  21. •• Balmer ML, Schurch CM, Saito Y, Geuking MB, Li H, Cuenca M, et al. Microbiota-derived compounds drive steady-state granulopoiesis via MyD88/TICAM signaling. J Immunol. 2014;193(10):5273–83. https://doi.org/10.4049/jimmunol.1400762. Uses germ-free and genotobiotic mice to establish, at steady state, the contribution of the microbiota in providing tonic stimulation to bone marrow stem and progenitor cells.

    Article  PubMed  CAS  Google Scholar 

  22. •• Iwamura C, Bouladoux N, Belkaid Y, Sher A, Jankovic D. Sensing of the microbiota by NOD1 in mesenchymal stromal cells regulates murine hematopoiesis. Blood. 2017;129(2):171–6. https://doi.org/10.1182/blood-2016-06-723742. Provides evidence of the role of the microbiota in regulating steady state hematopoiesis and establishes the contribution of Nod1 innate recognition pathway in this context.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  23. • Josefsdottir KS, Baldridge MT, Kadmon CS, King KY. Antibiotics impair murine hematopoiesis by depleting the intestinal microbiota. Blood. 2017;129(6):729–39. https://doi.org/10.1182/blood-2016-03-708594. Described the broad effect of a stringent antibiotic treatment on the hematopoietic compartment, suggesting a role of the microbiota on steady state hematopoiesis.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  24. Schuettpelz LG, Borgerding JN, Christopher MJ, Gopalan PK, Romine MP, Herman AC, et al. G-CSF regulates hematopoietic stem cell activity, in part, through activation of toll-like receptor signaling. Leukemia. 2014;28(9):1851–60. https://doi.org/10.1038/leu.2014.68.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  25. Gomez de Aguero M, Ganal-Vonarburg SC, Fuhrer T, Rupp S, Uchimura Y, Li H, et al. The maternal microbiota drives early postnatal innate immune development. Science. 2016;351(6279):1296–302. https://doi.org/10.1126/science.aad2571.

    Article  PubMed  Google Scholar 

  26. •• Cabezas-Wallscheid N, Buettner F, Sommerkamp P, Klimmeck D, Ladel L, Thalheimer FB, et al. Vitamin A-retinoic acid signaling regulates hematopoietic stem cell dormancy. Cell. 2017;169(5):807–23.e19. https://doi.org/10.1016/j.cell.2017.04.018. Uses single-cell RNA analyses to establish the heterogeneity of the quiescent HSC compartment and uncover a continuum of intermediate states from dormant HSCs to quiescent HSCs prone to activation. Proposes that this heterogeneity may reflect latent or past inflammatory events.

    Article  PubMed  CAS  Google Scholar 

  27. Cabezas-Wallscheid N, Klimmeck D, Hansson J, Lipka DB, Reyes A, Wang Q, et al. Identification of regulatory networks in HSCs and their immediate progeny via integrated proteome, transcriptome, and DNA methylome analysis. Cell Stem Cell. 2014;15(4):507–22. https://doi.org/10.1016/j.stem.2014.07.005.

    Article  PubMed  CAS  Google Scholar 

  28. Wilson A, Laurenti E, Oser G, van der Wath RC, Blanco-Bose W, Jaworski M, et al. Hematopoietic stem cells reversibly switch from dormancy to self-renewal during homeostasis and repair. Cell. 2008;135(6):1118–29. https://doi.org/10.1016/j.cell.2008.10.048.

    Article  PubMed  CAS  Google Scholar 

  29. Clarke TB, Davis KM, Lysenko ES, Zhou AY, Yu Y, Weiser JN. Recognition of peptidoglycan from the microbiota by Nod1 enhances systemic innate immunity. Nat Med. 2010;16(2):228–31. https://doi.org/10.1038/nm.2087.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  30. King KY, Goodell MA. Inflammatory modulation of HSCs: viewing the HSC as a foundation for the immune response. Nat Rev Immunol. 2011;11(10):685–92. https://doi.org/10.1038/nri3062.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  31. Mukaida N, Tanabe Y, Baba T. Chemokines as a conductor of bone marrow microenvironment in chronic myeloid leukemia. Int J Mol Sci. 2017;18(8) https://doi.org/10.3390/ijms18081824.

  32. Nagai Y, Garrett KP, Ohta S, Bahrun U, Kouro T, Akira S, et al. Toll-like receptors on hematopoietic progenitor cells stimulate innate immune system replenishment. Immunity. 2006;24(6):801–12. https://doi.org/10.1016/j.immuni.2006.04.008.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  33. Burberry A, Zeng MY, Ding L, Wicks I, Inohara N, Morrison SJ, et al. Infection mobilizes hematopoietic stem cells through cooperative NOD-like receptor and toll-like receptor signaling. Cell Host Microbe. 2014;15(6):779–91. https://doi.org/10.1016/j.chom.2014.05.004.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  34. Zhang H, Rodriguez S, Wang L, Wang S, Serezani H, Kapur R, et al. Sepsis induces hematopoietic stem cell exhaustion and Myelosuppression through distinct contributions of TRIF and MYD88. Stem Cell Reports. 2016;6(6):940–56. https://doi.org/10.1016/j.stemcr.2016.05.002.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  35. Fiedler K, Kokai E, Bresch S, Brunner C. MyD88 is involved in myeloid as well as lymphoid hematopoiesis independent of the presence of a pathogen. Am J Blood Res. 2013;3(2):124–40.

    PubMed  PubMed Central  CAS  Google Scholar 

  36. Ichii M, Shimazu T, Welner RS, Garrett KP, Zhang Q, Esplin BL, et al. Functional diversity of stem and progenitor cells with B-lymphopoietic potential. Immunol Rev. 2010;237(1):10–21. https://doi.org/10.1111/j.1600-065X.2010.00933.x.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  37. Liu A, Wang Y, Ding Y, Baez I, Payne KJ, Borghesi L. Cutting edge: hematopoietic stem cell expansion and common lymphoid progenitor depletion require hematopoietic-derived, cell-autonomous TLR4 in a model of chronic endotoxin. J Immunol. 2015;195(6):2524–8. https://doi.org/10.4049/jimmunol.1501231.

    Article  PubMed  CAS  Google Scholar 

  38. Pietras EM, Mirantes-Barbeito C, Fong S, Loeffler D, Kovtonyuk LV, Zhang S, et al. Chronic interleukin-1 exposure drives haematopoietic stem cells towards precocious myeloid differentiation at the expense of self-renewal. Nat Cell Biol. 2016;18(6):607–18. https://doi.org/10.1038/ncb3346.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  39. Pronk CJ, Veiby OP, Bryder D, Jacobsen SE. Tumor necrosis factor restricts hematopoietic stem cell activity in mice: involvement of two distinct receptors. J Exp Med. 2011;208(8):1563–70. https://doi.org/10.1084/jem.20110752.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  40. Baldridge MT, King KY, Boles NC, Weksberg DC, Goodell MA. Quiescent haematopoietic stem cells are activated by IFN-gamma in response to chronic infection. Nature. 2010;465(7299):793–7. https://doi.org/10.1038/nature09135.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  41. Essers MA, Offner S, Blanco-Bose WE, Waibler Z, Kalinke U, Duchosal MA, et al. IFNalpha activates dormant haematopoietic stem cells in vivo. Nature. 2009;458(7240):904–8. https://doi.org/10.1038/nature07815.

    Article  PubMed  CAS  Google Scholar 

  42. Hartner JC, Walkley CR, Lu J, Orkin SH. ADAR1 is essential for the maintenance of hematopoiesis and suppression of interferon signaling. Nat Immunol. 2009;10(1):109–15. https://doi.org/10.1038/ni.1680.

    Article  PubMed  CAS  Google Scholar 

  43. King KY, Baldridge MT, Weksberg DC, Chambers SM, Lukov GL, Wu S, et al. Irgm1 protects hematopoietic stem cells by negative regulation of IFN signaling. Blood. 2011;118(6):1525–33. https://doi.org/10.1182/blood-2011-01-328682.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  44. Sato T, Onai N, Yoshihara H, Arai F, Suda T, Ohteki T. Interferon regulatory factor-2 protects quiescent hematopoietic stem cells from type I interferon-dependent exhaustion. Nat Med. 2009;15(6):696–700. https://doi.org/10.1038/nm.1973.

    Article  PubMed  CAS  Google Scholar 

  45. de Bruin AM, Voermans C, Nolte MA. Impact of interferon-gamma on hematopoiesis. Blood. 2014;124(16):2479–86. https://doi.org/10.1182/blood-2014-04-568451.

    Article  PubMed  CAS  Google Scholar 

  46. Bottero V, Withoff S, Verma IM. NF-kappaB and the regulation of hematopoiesis. Cell Death Differ. 2006;13(5):785–97. https://doi.org/10.1038/sj.cdd.4401888.

    Article  PubMed  CAS  Google Scholar 

  47. Gonzalez-Murillo A, Fernandez L, Baena S, Melen GJ, Sanchez R, Sanchez-Valdepenas C, et al. The NFKB inducing kinase modulates hematopoiesis during stress. Stem Cells. 2015;33(9):2825–37. https://doi.org/10.1002/stem.2066.

    Article  PubMed  CAS  Google Scholar 

  48. Stein SJ, Baldwin AS. Deletion of the NF-kappaB subunit p65/RelA in the hematopoietic compartment leads to defects in hematopoietic stem cell function. Blood. 2013;121(25):5015–24. https://doi.org/10.1182/blood-2013-02-486142.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  49. Zhang J, Li L, Baldwin AS Jr, Friedman AD, Paz-Priel I. Loss of IKKbeta but not NF-kappaB p65 skews differentiation towards myeloid over Erythroid commitment and increases myeloid progenitor self-renewal and functional long-term hematopoietic stem cells. PLoS One. 2015;10(6):e0130441. https://doi.org/10.1371/journal.pone.0130441.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  50. Zhao C, Xiu Y, Ashton J, Xing L, Morita Y, Jordan CT, et al. Noncanonical NF-kappaB signaling regulates hematopoietic stem cell self-renewal and microenvironment interactions. Stem Cells. 2012;30(4):709–18. https://doi.org/10.1002/stem.1050.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  51. Adler BJ, Kaushansky K, Rubin CT. Obesity-driven disruption of haematopoiesis and the bone marrow niche. Nat Rev Endocrinol. 2014;10(12):737–48. https://doi.org/10.1038/nrendo.2014.169.

    Article  PubMed  CAS  Google Scholar 

  52. Akunuru S, Geiger H. Aging, clonality, and rejuvenation of hematopoietic stem cells. Trends Mol Med. 2016;22(8):701–12. https://doi.org/10.1016/j.molmed.2016.06.003.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  53. Lee JM, Govindarajah V, Goddard B, Hinge A, Muench DE, Filippi MD, et al. Obesity alters the long-term fitness of the hematopoietic stem cell compartment through modulation of Gfi1 expression. J Exp Med. 2017;215:627–44. https://doi.org/10.1084/jem.20170690.

    Article  PubMed  CAS  Google Scholar 

  54. Rossi DJ, Bryder D, Zahn JM, Ahlenius H, Sonu R, Wagers AJ, et al. Cell intrinsic alterations underlie hematopoietic stem cell aging. Proc Natl Acad Sci U S A. 2005;102(26):9194–9. https://doi.org/10.1073/pnas.0503280102.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  55. Gregor MF, Hotamisligil GS. Inflammatory mechanisms in obesity. Annu Rev Immunol. 2011;29:415–45. https://doi.org/10.1146/annurev-immunol-031210-101322.

    Article  PubMed  CAS  Google Scholar 

  56. Kovtonyuk LV, Fritsch K, Feng X, Manz MG, Takizawa H. Inflamm-aging of hematopoiesis, hematopoietic stem cells, and the bone marrow microenvironment. Front Immunol. 2016;7:502. https://doi.org/10.3389/fimmu.2016.00502.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  57. Claesson MJ, Cusack S, O'Sullivan O, Greene-Diniz R, de Weerd H, Flannery E, et al. Composition, variability, and temporal stability of the intestinal microbiota of the elderly. Proc Natl Acad Sci U S A. 2011;108(Suppl 1):4586–91. https://doi.org/10.1073/pnas.1000097107.

    Article  PubMed  CAS  Google Scholar 

  58. Turnbaugh PJ, Backhed F, Fulton L, Gordon JI. Diet-induced obesity is linked to marked but reversible alterations in the mouse distal gut microbiome. Cell Host Microbe. 2008;3(4):213–23. https://doi.org/10.1016/j.chom.2008.02.015.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  59. Cani PD, Amar J, Iglesias MA, Poggi M, Knauf C, Bastelica D, et al. Metabolic endotoxemia initiates obesity and insulin resistance. Diabetes. 2007;56(7):1761–72. https://doi.org/10.2337/db06-1491.

    Article  PubMed  CAS  Google Scholar 

  60. Stehle JR Jr, Leng X, Kitzman DW, Nicklas BJ, Kritchevsky SB, High KP. Lipopolysaccharide-binding protein, a surrogate marker of microbial translocation, is associated with physical function in healthy older adults. J Gerontol A Biol Sci Med Sci. 2012;67(11):1212–8. https://doi.org/10.1093/gerona/gls178.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  61. Esplin BL, Shimazu T, Welner RS, Garrett KP, Nie L, Zhang Q, et al. Chronic exposure to a TLR ligand injures hematopoietic stem cells. J Immunol. 2011;186(9):5367–75. https://doi.org/10.4049/jimmunol.1003438.

    Article  PubMed  CAS  Google Scholar 

  62. • Takizawa H, Fritsch K, Kovtonyuk LV, Saito Y, Yakkala C, Jacobs K, et al. Pathogen-induced TLR4-TRIF innate immune signaling in hematopoietic stem cells promotes proliferation but reduces competitive fitness. Cell Stem Cell. 2017;21(2):225–40.e5. https://doi.org/10.1016/j.stem.2017.06.013. Establishes in vivo the molecular mechanisms by which TLR signaling directly impacts of the fitness of the HSC compartment.

    Article  PubMed  CAS  Google Scholar 

  63. • Kobayashi H, Suda T, Takubo K. How hematopoietic stem/progenitors and their niche sense and respond to infectious stress. Exp Hematol. 2016;44(2):92–100. https://doi.org/10.1016/j.exphem.2015.11.008. Comprehensive review of the impact of various infectious conditions on the hematopoietic stem and progenitor compartment.

    Article  PubMed  CAS  Google Scholar 

  64. Pietras EM. Inflammation: a key regulator of hematopoietic stem cell fate in health and disease. Blood. 2017;130(15):1693–8. https://doi.org/10.1182/blood-2017-06-780882.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  65. Takizawa H, Boettcher S, Manz MG. Demand-adapted regulation of early hematopoiesis in infection and inflammation. Blood. 2012;119(13):2991–3002. https://doi.org/10.1182/blood-2011-12-380113.

    Article  PubMed  CAS  Google Scholar 

  66. Pietras EM, Lakshminarasimhan R, Techner JM, Fong S, Flach J, Binnewies M, et al. Re-entry into quiescence protects hematopoietic stem cells from the killing effect of chronic exposure to type I interferons. J Exp Med. 2014;211(2):245–62. https://doi.org/10.1084/jem.20131043.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  67. Yamamoto R, Morita Y, Ooehara J, Hamanaka S, Onodera M, Rudolph KL, et al. Clonal analysis unveils self-renewing lineage-restricted progenitors generated directly from hematopoietic stem cells. Cell. 2013;154(5):1112–26. https://doi.org/10.1016/j.cell.2013.08.007.

    Article  PubMed  CAS  Google Scholar 

  68. Matatall KA, Shen CC, Challen GA, King KY. Type II interferon promotes differentiation of myeloid-biased hematopoietic stem cells. Stem Cells. 2014;32(11):3023–30. https://doi.org/10.1002/stem.1799.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  69. •• Haas S, Hansson J, Klimmeck D, Loeffler D, Velten L, Uckelmann H, et al. Inflammation-induced emergency Megakaryopoiesis driven by hematopoietic stem cell-like megakaryocyte progenitors. Cell Stem Cell. 2015;17(4):422–34. https://doi.org/10.1016/j.stem.2015.07.007. Describes the specific activation of an HSC-like compartment promoting the rapid and efficient platelet recovery after inflammation-induced thrombocytopenia.

    Article  PubMed  CAS  Google Scholar 

  70. Taniguchi T, Takaoka A. A weak signal for strong responses: interferon-alpha/beta revisited. Nat Rev Mol Cell Biol. 2001;2(5):378–86. https://doi.org/10.1038/35073080.

    Article  PubMed  CAS  Google Scholar 

  71. Massberg S, Schaerli P, Knezevic-Maramica I, Kollnberger M, Tubo N, Moseman EA, et al. Immunosurveillance by hematopoietic progenitor cells trafficking through blood, lymph, and peripheral tissues. Cell. 2007;131(5):994–1008. https://doi.org/10.1016/j.cell.2007.09.047.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  72. Kristinsson SY, Bjorkholm M, Hultcrantz M, Derolf AR, Landgren O, Goldin LR. Chronic immune stimulation might act as a trigger for the development of acute myeloid leukemia or myelodysplastic syndromes. J Clin Oncol. 2011;29(21):2897–903. https://doi.org/10.1200/jco.2011.34.8540.

    Article  PubMed  PubMed Central  Google Scholar 

  73. Kristinsson SY, Landgren O, Samuelsson J, Bjorkholm M, Goldin LR. Autoimmunity and the risk of myeloproliferative neoplasms. Haematologica. 2010;95(7):1216–20. https://doi.org/10.3324/haematol.2009.020412.

    Article  PubMed  PubMed Central  Google Scholar 

  74. Larsson SC, Wolk A. Overweight and obesity and incidence of leukemia: a meta-analysis of cohort studies. Int J Cancer. 2008;122(6):1418–21. https://doi.org/10.1002/ijc.23176.

    Article  PubMed  CAS  Google Scholar 

  75. Lichtman MA, Rowe JM. The relationship of patient age to the pathobiology of the clonal myeloid diseases. Semin Oncol. 2004;31(2):185–97.

    Article  PubMed  Google Scholar 

  76. Williamson BT, Foltz L, Leitch HA. Autoimmune syndromes presenting as a paraneoplastic manifestation of Myelodysplastic syndromes: clinical features, course, Treatment and Outcome. Hematol Rep. 2016;8(2):6480. https://doi.org/10.4081/hr.2016.6480.

    Article  PubMed  PubMed Central  Google Scholar 

  77. Hemmati S, Haque T, Gritsman K. Inflammatory signaling pathways in preleukemic and leukemic stem cells. Front Oncol. 2017;7:265. https://doi.org/10.3389/fonc.2017.00265.

    Article  PubMed  PubMed Central  Google Scholar 

  78. • Zambetti NA, Ping Z, Chen S, Kenswil KJ, Mylona MA, Sanders MA, et al. Mesenchymal inflammation drives genotoxic stress in hematopoietic stem cells and predicts disease evolution in human pre-leukemia. Cell Stem Cell. 2016;19(5):613–27. https://doi.org/10.1016/j.stem.2016.08.021. Shows how mutations in the bone marrow niche could lead to the development of an inflammatory environment that promotes HSC genotoxic stress and increases the risk of leukemic transformation.

    Article  PubMed  CAS  Google Scholar 

  79. Walter D, Lier A, Geiselhart A, Thalheimer FB, Huntscha S, Sobotta MC, et al. Exit from dormancy provokes DNA-damage-induced attrition in haematopoietic stem cells. Nature. 2015;520(7548):549–52. https://doi.org/10.1038/nature14131.

    Article  PubMed  CAS  Google Scholar 

  80. Fang J, Bolanos LC, Choi K, Liu X, Christie S, Akunuru S, et al. Ubiquitination of hnRNPA1 by TRAF6 links chronic innate immune signaling with myelodysplasia. Nat Immunol. 2017;18(2):236–45. https://doi.org/10.1038/ni.3654.

    Article  PubMed  CAS  Google Scholar 

  81. Jiang Q, Crews LA, Barrett CL, Chun HJ, Court AC, Isquith JM, et al. ADAR1 promotes malignant progenitor reprogramming in chronic myeloid leukemia. Proc Natl Acad Sci U S A. 2013;110(3):1041–6. https://doi.org/10.1073/pnas.1213021110.

    Article  PubMed  CAS  Google Scholar 

  82. Busque L, Patel JP, Figueroa ME, Vasanthakumar A, Provost S, Hamilou Z, et al. Recurrent somatic TET2 mutations in normal elderly individuals with clonal hematopoiesis. Nat Genet. 2012;44(11):1179–81. https://doi.org/10.1038/ng.2413.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  83. Genovese G, Kahler AK, Handsaker RE, Lindberg J, Rose SA, Bakhoum SF, et al. Clonal hematopoiesis and blood-cancer risk inferred from blood DNA sequence. N Engl J Med. 2014;371(26):2477–87. https://doi.org/10.1056/NEJMoa1409405.

    Article  PubMed  PubMed Central  Google Scholar 

  84. Jaiswal S, Fontanillas P, Flannick J, Manning A, Grauman PV, Mar BG, et al. Age-related clonal hematopoiesis associated with adverse outcomes. N Engl J Med. 2014;371(26):2488–98. https://doi.org/10.1056/NEJMoa1408617.

    Article  PubMed  PubMed Central  Google Scholar 

  85. Jan M, Ebert BL, Jaiswal S. Clonal hematopoiesis. Semin Hematol. 2017;54(1):43–50. https://doi.org/10.1053/j.seminhematol.2016.10.002.

    Article  PubMed  Google Scholar 

  86. Cooper JN, Young NS. Clonality in context: hematopoietic clones in their marrow environment. Blood. 2017;130(22):2363–72. https://doi.org/10.1182/blood-2017-07-794362.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  87. Steensma DP, Bejar R, Jaiswal S, Lindsley RC, Sekeres MA, Hasserjian RP, et al. Clonal hematopoiesis of indeterminate potential and its distinction from myelodysplastic syndromes. Blood. 2015;126(1):9–16. https://doi.org/10.1182/blood-2015-03-631747.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  88. Cull AH, Snetsinger B, Buckstein R, Wells RA, Rauh MJ. Tet2 restrains inflammatory gene expression in macrophages. Exp Hematol. 2017;55:56–70.e13. https://doi.org/10.1016/j.exphem.2017.08.001.

    Article  PubMed  CAS  Google Scholar 

  89. Leoni C, Montagner S, Rinaldi A, Bertoni F, Polletti S, Balestrieri C, et al. Dnmt3a restrains mast cell inflammatory responses. Proc Natl Acad Sci U S A. 2017;114(8):E1490–e9. https://doi.org/10.1073/pnas.1616420114.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  90. •• Fuster JJ, MacLauchlan S, Zuriaga MA, Polackal MN, Ostriker AC, Chakraborty R, et al. Clonal hematopoiesis associated with TET2 deficiency accelerates atherosclerosis development in mice. Science. 2017;355(6327):842–7. https://doi.org/10.1126/science.aag1381. Demonstrates in mouse model that clonal hematopoiesis associated with TET2 mutation leads to inflammation and contributes to exacerbated atherosclerosis.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  91. •• Jaiswal S, Natarajan P, Silver AJ, Gibson CJ, Bick AG, Shvartz E, et al. Clonal hematopoiesis and risk of atherosclerotic cardiovascular disease. N Engl J Med. 2017;377(2):111–21. https://doi.org/10.1056/NEJMoa1701719. Complementary to Fuster et al. Indicates that somatic mutations in hematopoietic cells contribute to the development of human atherosclerosis through the activation of specific inflammatory pathways.

    Article  PubMed  PubMed Central  Google Scholar 

  92. Link DC, Walter MJ. 'CHIP'ping away at clonal hematopoiesis. Leukemia. 2016;30(8):1633–5. https://doi.org/10.1038/leu.2016.130.

    Article  PubMed  CAS  Google Scholar 

  93. Abegunde SO, Buckstein R, Wells RA, Rauh MJ. An inflammatory environment containing TNFalpha favors Tet2-mutant clonal hematopoiesis. Exp Hematol. 2018; https://doi.org/10.1016/j.exphem.2017.11.002.

  94. •• Beura LK, Hamilton SE, Bi K, Schenkel JM, Odumade OA, Casey KA, et al. Normalizing the environment recapitulates adult human immune traits in laboratory mice. Nature. 2016;532(7600):512–6. https://doi.org/10.1038/nature17655. Highlights the caveats associated with the use of experimental mouse model in aberrant hygienic conditions and the interest of the restoring normal environmental exposure for the modeling of immunological events.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  95. •• Reese TA, Bi K, Kambal A, Filali-Mouhim A, Beura LK, Burger MC, et al. Sequential infection with common pathogens promotes human-like immune gene expression and altered vaccine response. Cell Host Microbe. 2016;19(5):713–9. https://doi.org/10.1016/j.chom.2016.04.003. As in Beura et al., highlights the importance of providing natural immunological history to laboratory animals to better model human immunological system.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  96. Busch K, Klapproth K, Barile M, Flossdorf M, Holland-Letz T, Schlenner SM, et al. Fundamental properties of unperturbed haematopoiesis from stem cells in vivo. Nature. 2015;518(7540):542–6. https://doi.org/10.1038/nature14242.

    Article  PubMed  CAS  Google Scholar 

  97. Sawai CM, Babovic S, Upadhaya S, Knapp D, Lavin Y, Lau CM, et al. Hematopoietic stem cells are the major source of multilineage hematopoiesis in adult animals. Immunity. 2016;45(3):597–609. https://doi.org/10.1016/j.immuni.2016.08.007.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  98. Schoedel KB, Morcos MNF, 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(19):2285–96. https://doi.org/10.1182/blood-2016-03-706010.

    Article  PubMed  CAS  Google Scholar 

  99. Sun J, Ramos A, Chapman B, Johnnidis JB, Le L, Ho YJ, et al. Clonal dynamics of native haematopoiesis. Nature. 2014;514(7522):322–7. https://doi.org/10.1038/nature13824.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  100. Malam Z, Cohn RD. Stem cells on alert: priming quiescent stem cells after remote injury. Cell Stem Cell. 2014;15(1):7–8. https://doi.org/10.1016/j.stem.2014.06.012.

    Article  PubMed  CAS  Google Scholar 

  101. Rodgers JT, King KY, Brett JO, Cromie MJ, Charville GW, Maguire KK, et al. mTORC1 controls the adaptive transition of quiescent stem cells from G0 to G(alert). Nature. 2014;510(7505):393–6. https://doi.org/10.1038/nature13255.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  102. Kaufmann E, Sanz J, Dunn JL, Khan N, Mendonca LE, Pacis A, et al. BCG educates hematopoietic stem cells to generate protective innate immunity against tuberculosis. Cell. 2018;172(1–2):176–90.e19. https://doi.org/10.1016/j.cell.2017.12.031.

    Article  PubMed  CAS  Google Scholar 

  103. Mitroulis I, Ruppova K, Wang B, Chen LS, Grzybek M, Grinenko T, et al. Modulation of myelopoiesis progenitors is an integral component of trained immunity. Cell. 2018;172(1–2):147–61.e12. https://doi.org/10.1016/j.cell.2017.11.034.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  104. •• Rosshart SP, Vassallo BG, Angeletti D, Hutchinson DS, Morgan AP, Takeda K, et al. Wild mouse gut microbiota promotes host fitness and improves disease resistance. Cell. 2017;171(5):1015–28.e13. https://doi.org/10.1016/j.cell.2017.09.016. Demonstrates that the gut microbiota of laboratory mice markedly differs from wild populations and highlights the impact of this difference on the outcome of infectious diseases and cancers.

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Acknowledgments

The authors apologize to their colleagues whose original work could not be cited due to space limitations. The authors thank Drs. Jose Cancelas, Daniel Starczynowski and Gang Huang for critical reading of this review.

Funding

This work was supported by a National Institutes of Health grant (R01HL141418) and a DOD PRCRP award (DOD#W81XWH-15-1-0344).

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Authors and Affiliations

  1. Stem Cell Program, Division of Experimental Hematology and Cancer Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA

    Vinothini Govindarajah & Damien Reynaud

  2. Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA

    Damien Reynaud

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  1. Vinothini Govindarajah
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Correspondence to Damien Reynaud.

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Vinothini Govindarajah and Damien Reynaud declare that they have no conflict of interest.

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This article is part of the Topical Collection on Cancer and Stem Cells

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Govindarajah, V., Reynaud, D. Tuning of the Hematopoietic Stem Cell Compartment in its Inflammatory Environment. Curr Stem Cell Rep 4, 189–200 (2018). https://doi.org/10.1007/s40778-018-0131-y

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