Tuning of the Hematopoietic Stem Cell Compartment in its Inflammatory Environment
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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.
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.
KeywordsHematopoietic 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.
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
- 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. PubMedGoogle 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.PubMedPubMedCentralGoogle 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. PubMedGoogle 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. PubMedPubMedCentralGoogle 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. PubMedPubMedCentralGoogle 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. PubMedGoogle 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.PubMedGoogle 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.
- 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.PubMedPubMedCentralGoogle 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.PubMedPubMedCentralGoogle 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.PubMedPubMedCentralGoogle 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.PubMedPubMedCentralGoogle 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.PubMedPubMedCentralGoogle 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.PubMedGoogle 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.PubMedPubMedCentralGoogle 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. PubMedGoogle 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. PubMedGoogle 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.PubMedPubMedCentralGoogle 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. PubMedGoogle 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.PubMedPubMedCentralGoogle 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. PubMedPubMedCentralGoogle 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. PubMedGoogle 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.PubMedGoogle 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. PubMedPubMedCentralGoogle 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. PubMedGoogle 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. PubMedPubMedCentralGoogle 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. PubMedPubMedCentralGoogle 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.