Current Stem Cell Reports

, Volume 4, Issue 3, pp 189–200 | Cite as

Tuning of the Hematopoietic Stem Cell Compartment in its Inflammatory Environment

  • Vinothini Govindarajah
  • Damien ReynaudEmail author
Cancer and Stem Cells (D Starczynowski and G Huang, Section Editors)
Part of the following topical collections:
  1. Topical Collection on Cancer and Stem Cells


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.


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.


Hematopoietic stem cell Inflammation Aging Obesity Immunological history Hematological disease 



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 Information

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

Compliances with Ethical Standards

Conflict of Interest

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

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.


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

  1. 1.
    Medzhitov R. Origin and physiological roles of inflammation. Nature. 2008;454(7203):428–35. Scholar
  2. 2.
    Kauts ML, Vink CS, Dzierzak E. Hematopoietic (stem) cell development—how divergent are the roads taken? FEBS Lett. 2016;590(22):3975–86. Scholar
  3. 3.
    Clements WK, Traver D. Signalling pathways that control vertebrate haematopoietic stem cell specification. Nat Rev Immunol. 2013;13(5):336–48. Scholar
  4. 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. Detailed review of the inflammatory mechanisms contributing to HSC emergence in the embryo. PubMedCrossRefGoogle Scholar
  5. 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. Scholar
  6. 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. Scholar
  7. 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. Scholar
  8. 8.
    Sawamiphak S, Kontarakis Z, Stainier DY. Interferon gamma signaling positively regulates hematopoietic stem cell emergence. Dev Cell. 2014;31(5):640–53. Scholar
  9. 9.
    Funkhouser LJ, Bordenstein SR. Mom knows best: the universality of maternal microbial transmission. PLoS Biol. 2013;11(8):e1001631. Scholar
  10. 10.
    Basha S, Surendran N, Pichichero M. Immune responses in neonates. Expert Rev Clin Immunol. 2014;10(9):1171–84. Scholar
  11. 11.
    Copley MR, Eaves CJ. Developmental changes in hematopoietic stem cell properties. Exp Mol Med. 2013;45:e55. Scholar
  12. 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. Scholar
  13. 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. PubMedPubMedCentralCrossRefGoogle Scholar
  14. 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. Scholar
  15. 15.
    Turnbaugh PJ, Ley RE, Hamady M, Fraser-Liggett CM, Knight R, Gordon JI. The human microbiome project. Nature. 2007;449(7164):804–10. Scholar
  16. 16.
    •• Kundu P, Blacher E, Elinav E, Pettersson S. Our gut microbiome: the evolving inner self. Cell. 2017;171(7):1481–93. Comprehensive review of the evolving relationship of the gut microbiota with its host across human lifespan. PubMedCrossRefGoogle Scholar
  17. 17.
    Chow J, Lee SM, Shen Y, Khosravi A, Mazmanian SK. Host-bacterial symbiosis in health and disease. Adv Immunol. 2010;107:243–74. Scholar
  18. 18.
    Manzo VE, Bhatt AS. The human microbiome in hematopoiesis and hematologic disorders. Blood. 2015;126(3):311–8. Scholar
  19. 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. Scholar
  20. 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. Scholar
  21. 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. 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. PubMedCrossRefGoogle Scholar
  22. 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. 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. PubMedPubMedCentralCrossRefGoogle Scholar
  23. 23.
    • Josefsdottir KS, Baldridge MT, Kadmon CS, King KY. Antibiotics impair murine hematopoiesis by depleting the intestinal microbiota. Blood. 2017;129(6):729–39. Described the broad effect of a stringent antibiotic treatment on the hematopoietic compartment, suggesting a role of the microbiota on steady state hematopoiesis. PubMedPubMedCentralCrossRefGoogle Scholar
  24. 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. Scholar
  25. 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. PubMedCrossRefGoogle Scholar
  26. 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. 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. PubMedCrossRefGoogle Scholar
  27. 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. Scholar
  28. 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. Scholar
  29. 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. Scholar
  30. 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. Scholar
  31. 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)
  32. 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. Scholar
  33. 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. Scholar
  34. 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. Scholar
  35. 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.PubMedPubMedCentralGoogle Scholar
  36. 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. Scholar
  37. 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. Scholar
  38. 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. Scholar
  39. 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. Scholar
  40. 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. Scholar
  41. 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. PubMedCrossRefPubMedCentralGoogle Scholar
  42. 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. Scholar
  43. 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. Scholar
  44. 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. Scholar
  45. 45.
    de Bruin AM, Voermans C, Nolte MA. Impact of interferon-gamma on hematopoiesis. Blood. 2014;124(16):2479–86. Scholar
  46. 46.
    Bottero V, Withoff S, Verma IM. NF-kappaB and the regulation of hematopoiesis. Cell Death Differ. 2006;13(5):785–97. PubMedCrossRefGoogle Scholar
  47. 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. PubMedCrossRefGoogle Scholar
  48. 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. Scholar
  49. 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. Scholar
  50. 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. PubMedPubMedCentralCrossRefGoogle Scholar
  51. 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. Scholar
  52. 52.
    Akunuru S, Geiger H. Aging, clonality, and rejuvenation of hematopoietic stem cells. Trends Mol Med. 2016;22(8):701–12. Scholar
  53. 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. Scholar
  54. 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. PubMedPubMedCentralCrossRefGoogle Scholar
  55. 55.
    Gregor MF, Hotamisligil GS. Inflammatory mechanisms in obesity. Annu Rev Immunol. 2011;29:415–45. Scholar
  56. 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. Scholar
  57. 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. PubMedCrossRefGoogle Scholar
  58. 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. Scholar
  59. 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. Scholar
  60. 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. Scholar
  61. 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. Scholar
  62. 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. Establishes in vivo the molecular mechanisms by which TLR signaling directly impacts of the fitness of the HSC compartment. PubMedCrossRefGoogle Scholar
  63. 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. Comprehensive review of the impact of various infectious conditions on the hematopoietic stem and progenitor compartment. PubMedCrossRefGoogle Scholar
  64. 64.
    Pietras EM. Inflammation: a key regulator of hematopoietic stem cell fate in health and disease. Blood. 2017;130(15):1693–8. Scholar
  65. 65.
    Takizawa H, Boettcher S, Manz MG. Demand-adapted regulation of early hematopoiesis in infection and inflammation. Blood. 2012;119(13):2991–3002. Scholar
  66. 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. Scholar
  67. 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. Scholar
  68. 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. PubMedPubMedCentralCrossRefGoogle Scholar
  69. 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. Describes the specific activation of an HSC-like compartment promoting the rapid and efficient platelet recovery after inflammation-induced thrombocytopenia. PubMedCrossRefGoogle Scholar
  70. 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. Scholar
  71. 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. Scholar
  72. 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. PubMedPubMedCentralCrossRefGoogle Scholar
  73. 73.
    Kristinsson SY, Landgren O, Samuelsson J, Bjorkholm M, Goldin LR. Autoimmunity and the risk of myeloproliferative neoplasms. Haematologica. 2010;95(7):1216–20. Scholar
  74. 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. Scholar
  75. 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.PubMedCrossRefGoogle Scholar
  76. 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. PubMedPubMedCentralCrossRefGoogle Scholar
  77. 77.
    Hemmati S, Haque T, Gritsman K. Inflammatory signaling pathways in preleukemic and leukemic stem cells. Front Oncol. 2017;7:265. Scholar
  78. 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. 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. PubMedCrossRefGoogle Scholar
  79. 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. Scholar
  80. 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. PubMedCrossRefGoogle Scholar
  81. 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. PubMedCrossRefGoogle Scholar
  82. 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. Scholar
  83. 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. PubMedPubMedCentralCrossRefGoogle Scholar
  84. 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. PubMedPubMedCentralCrossRefGoogle Scholar
  85. 85.
    Jan M, Ebert BL, Jaiswal S. Clonal hematopoiesis. Semin Hematol. 2017;54(1):43–50. Scholar
  86. 86.
    Cooper JN, Young NS. Clonality in context: hematopoietic clones in their marrow environment. Blood. 2017;130(22):2363–72. Scholar
  87. 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. Scholar
  88. 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. Scholar
  89. 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. PubMedPubMedCentralCrossRefGoogle Scholar
  90. 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. Demonstrates in mouse model that clonal hematopoiesis associated with TET2 mutation leads to inflammation and contributes to exacerbated atherosclerosis. PubMedPubMedCentralCrossRefGoogle Scholar
  91. 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. 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. PubMedCrossRefGoogle Scholar
  92. 92.
    Link DC, Walter MJ. 'CHIP'ping away at clonal hematopoiesis. Leukemia. 2016;30(8):1633–5. Scholar
  93. 93.
    Abegunde SO, Buckstein R, Wells RA, Rauh MJ. An inflammatory environment containing TNFalpha favors Tet2-mutant clonal hematopoiesis. Exp Hematol. 2018;
  94. 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. 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. PubMedPubMedCentralCrossRefGoogle Scholar
  95. 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. As in Beura et al., highlights the importance of providing natural immunological history to laboratory animals to better model human immunological system. PubMedPubMedCentralCrossRefGoogle Scholar
  96. 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. Scholar
  97. 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. Scholar
  98. 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. Scholar
  99. 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. Scholar
  100. 100.
    Malam Z, Cohn RD. Stem cells on alert: priming quiescent stem cells after remote injury. Cell Stem Cell. 2014;15(1):7–8. Scholar
  101. 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. Scholar
  102. 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. Scholar
  103. 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. Scholar
  104. 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. 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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© Springer Nature Switzerland AG 2018

Authors and Affiliations

  1. 1.Stem Cell Program, Division of Experimental Hematology and Cancer BiologyCincinnati Children’s Hospital Medical CenterCincinnatiUSA
  2. 2.Department of PediatricsUniversity of Cincinnati College of MedicineCincinnatiUSA

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