The core function of hematopoietic stem and progenitor cells (HSPCs) is to provide lifelong production of all lineages of the blood and immune cells. The mechanisms that modulate HSPC homeostasis and lineage biasing are not fully understood. Growing evidence implicates the aryl hydrocarbon receptor (AHR), an environment-sensing transcription factor, as a regulator of hematopoiesis. AHR ligands modulate the frequency of mature hematopoietic cells in the bone marrow and periphery, while HSPCs from mice lacking AHR (AHR KO) have increased proliferation. Yet, whether AHR modulates HSPC lineage potential and directs differentiation toward specific lineage-biased progenitors is not well understood. This study revealed that AHR KO mice have an increased proportion of myeloid-biased HSCs and myeloid-biased multipotent progenitor (MPP3) cells. Utilizing inducible AHR knockout mice (iAHR KO), it was discovered that acute deletion of AHR doubled the number of MPP3 cells and altered the composition of downstream lineage-committed progenitors, such as increased frequency of pregranulocyte/premonocyte committed progenitors. Furthermore, in vivo antagonism of the AHR led to a 2.5-fold increase in the number of MPP3 cells and promoted myeloid-biased differentiation. Using hematopoietic-specific conditional AHR knockout mice (AHRVav1) revealed that increased frequency of myeloid-biased HSCs and myeloid-biased progenitors is driven by AHR signaling that is intrinsic to the hematopoietic compartment. These findings demonstrate that the AHR plays a pivotal role in regulating steady-state hematopoiesis, influencing HSPC homeostasis and lineage potential. In addition, the data presented provide potential insight into how deliberate modulation of AHR signaling could help with the treatment of a broad range of diseases that require the hematopoietic compartment.
Get full access to this article
View all access options for this article.
References
1.
OrkinSH and ZonLI. (2008). Hematopoiesis: an evolving paradigm for stem cell biology. Cell, 132:631–644.
2.
EssersMA, OffnerS, Blanco-BoseWE, WaiblerZ, KalinkeU, DuchosalMA and TrumppA. (2009). IFNalpha activates dormant haematopoietic stem cells in vivo. Nature, 458:904–908.
3.
KingKY and GoodellMA. (2011). Inflammatory modulation of HSCs: viewing the HSC as a foundation for the immune response. Nat Rev Immunol, 11:685–692.
4.
Cabezas-WallscheidN, KlimmeckD, HanssonJ, LipkaDB, ReyesA, WangQ, WeichenhanD, LierA, von PaleskeL, et al. (2014). Identification of regulatory networks in HSCs and their immediate progeny via integrated proteome, transcriptome, and DNA methylome analysis. Cell Stem Cell, 15:507–522.
5.
PietrasEM, ReynaudD, KangYA, CarlinD, Calero-NietoFJ, LeavittAD, StuartJM, GottgensB and PassegueE. (2015). Functionally distinct subsets of lineage-biased multipotent progenitors control blood production in normal and regenerative conditions. Cell Stem Cell, 17:35–46.
6.
YeM, ZhangH, YangH, KocheR, StaberPB, CusanM, LevantiniE, WelnerRS, BachCS, et al. (2015). Hematopoietic differentiation is required for initiation of acute myeloid leukemia. Cell Stem Cell, 17:611–623.
7.
ShastriA, WillB, SteidlU and VermaA. (2017). Stem and progenitor cell alterations in myelodysplastic syndromes. Blood, 129:1586–1594.
8.
WilkinsonAC and GottgensB. (2013). Transcriptional regulation of haematopoietic stem cells. Adv Exp Med Biol, 786:187–212.
9.
EsserC and RannugA. (2015). The aryl hydrocarbon receptor in barrier organ physiology, immunology, and toxicology. Pharmacol Rev, 67:259–279.
10.
SoshilovAA and DenisonMS. (2014). Ligand promiscuity of aryl hydrocarbon receptor agonists and antagonists revealed by site-directed mutagenesis. Mol Cell Biol, 34:1707–1719.
GarrettRW and GasiewiczTA. (2006). The aryl hydrocarbon receptor agonist 2,3,7,8-tetrachlorodibenzo-p-dioxin alters the circadian rhythms, quiescence, and expression of clock genes in murine hematopoietic stem and progenitor cells. Mol Pharmacol, 69:2076–2083.
13.
SmithBW, RozelleSS, LeungA, UbellackerJ, ParksA, NahSK, FrenchD, GadueP, MontiS, et al. (2013). The aryl hydrocarbon receptor directs hematopoietic progenitor cell expansion and differentiation. Blood, 122:376–385.
14.
(1997). IARC Working Group on the Evaluation of Carcinogenic Risks to Humans: Polychlorinated Dibenzo-Para-Dioxins and Polychlorinated Dibenzofurans. Lyon, France, 4–11 February 1997. IARC Monogr Eval Carcinog Risks Hum 69:1–631.
15.
BertazziPA, ConsonniD, BachettiS, RubagottiM, BaccarelliA, ZocchettiC and PesatoriAC. (2001). Health effects of dioxin exposure: a 20-year mortality study. Am J Epidemiol, 153:1031–1044.
16.
KramerS, HikelSM, AdamsK, HindsD and MoonK. (2012). Current status of the epidemiologic evidence linking polychlorinated biphenyls and non-hodgkin lymphoma, and the role of immune dysregulation. Environ Health Perspect, 120:1067–1075.
17.
BoitanoAE, WangJ, RomeoR, BouchezLC, ParkerAE, SuttonSE, WalkerJR, FlavenyCA, PerdewGH, et al. (2010). Aryl hydrocarbon receptor antagonists promote the expansion of human hematopoietic stem cells. Science, 329:1345–1348.
18.
ThurmondTS, StaplesJE, SilverstoneAE and GasiewiczTA. (2000). The aryl hydrocarbon receptor has a role in the in vivo maturation of murine bone marrow B lymphocytes and their response to 2,3,7,8-tetrachlorodibenzo-p-dioxin. Toxicol Appl Pharmacol, 165:227–236.
19.
BankotiJ, BurnettA, NavarroS, MillerAK, RaseB and ShepherdDM. (2010). Effects of TCDD on the fate of naive dendritic cells. Toxicol Sci, 115:422–434.
20.
BouleLA, BurkeCG, JinGB and LawrenceBP. (2018). Aryl hydrocarbon receptor signaling modulates antiviral immune responses: ligand metabolism rather than chemical source is the stronger predictor of outcome. Sci Rep, 8:1826.
21.
SinghKP, GarrettRW, CasadoFL and GasiewiczTA. (2011). Aryl hydrocarbon receptor-null allele mice have hematopoietic stem/progenitor cells with abnormal characteristics and functions. Stem Cells Dev, 20:769–784.
22.
UnnisaZ, SinghKP, HenryEC, DoneganCL, BennettJA and GasiewiczTA. (2016). Aryl hydrocarbon receptor deficiency in an Exon 3 deletion mouse model promotes hematopoietic stem cell proliferation and impacts endosteal niche cells. Stem Cells Int, 2016:4536187.
23.
GasiewiczTA, SinghKP and BennettJA. (2014). The Ah receptor in stem cell cycling, regulation, and quiescence. Ann N Y Acad Sci, 1310:44–50.
24.
LindseyS and PapoutsakisET. (2012). The evolving role of the aryl hydrocarbon receptor (AHR) in the normophysiology of hematopoiesis. Stem Cell Rev Rep, 8:1223–1235.
25.
BennettJA, SinghKP, WelleSL, BouleLA, LawrenceBP and GasiewiczTA. (2018). Conditional deletion of Ahr alters gene expression profiles in hematopoietic stem cells. PLoS One, 13:e0206407.
26.
SchmidtJV, SuGH, ReddyJK, SimonMC and BradfieldCA. (1996). Characterization of a murine Ahr null allele: involvement of the Ah receptor in hepatic growth and development. Proc Natl Acad Sci U S A, 93:6731–6736.
27.
WalisserJA, GloverE, PandeK, LissAL and BradfieldCA. (2005). Aryl hydrocarbon receptor-dependent liver development and hepatotoxicity are mediated by different cell types. Proc Natl Acad Sci U S A, 102:17858–17863.
28.
FeilR, BrocardJ, MascrezB, LeMeurM, MetzgerD and ChambonP. (1996). Ligand-activated site-specific recombination in mice. Proc Natl Acad Sci U S A, 93:10887–10890.
29.
VanniniN, CamposV, GirotraM, TrachselV, Rojas-SutterlinS, TratwalJ, RagusaS, StefanidisE, RyuD, et al. (2019). The NAD-booster nicotinamide riboside potently stimulates hematopoiesis through increased mitochondrial clearance. Cell Stem Cell, 24:405–418 e7.
30.
BeermanI, BhattacharyaD, ZandiS, SigvardssonM, WeissmanIL, BryderD and RossiDJ. (2010). Functionally distinct hematopoietic stem cells modulate hematopoietic lineage potential during aging by a mechanism of clonal expansion. Proc Natl Acad Sci U S A, 107:5465–5470.
31.
ZhaoB, DegrootDE, HayashiA, HeG and DenisonMS. (2010). CH223191 is a ligand-selective antagonist of the Ah (Dioxin) receptor. Toxicol Sci, 117:393–403.
32.
FrericksM, MeissnerM and EsserC. (2007). Microarray analysis of the AHR system: tissue-specific flexibility in signal and target genes. Toxicol Appl Pharmacol, 220:320–332.
33.
WheelerJL, MartinKC, ResseguieE and LawrenceBP. (2014). Differential consequences of two distinct AhR ligands on innate and adaptive immune responses to influenza A virus. Toxicol Sci, 137:324–334.
34.
NegishiT, KatoY, OonedaO, MimuraJ, TakadaT, MochizukiH, YamamotoM, Fujii-KuriyamaY and FurusakoS. (2005). Effects of aryl hydrocarbon receptor signaling on the modulation of TH1/TH2 balance. J Immunol, 175:7348–7356.
35.
CasadoFL, SinghKP and GasiewiczTA. (2011). Aryl hydrocarbon receptor activation in hematopoietic stem/progenitor cells alters cell function and pathway-specific gene modulation reflecting changes in cellular trafficking and migration. Mol Pharmacol, 80:673–682.
36.
SinghKP, WymanA, CasadoFL, GarrettRW and GasiewiczTA. (2009). Treatment of mice with the Ah receptor agonist and human carcinogen dioxin results in altered numbers and function of hematopoietic stem cells. Carcinogenesis, 30:11–19.
37.
SakaiR, KajiumeT, InoueH, KannoR, MiyazakiM, NinomiyaY and KannoM. (2003). TCDD treatment eliminates the long-term reconstitution activity of hematopoietic stem cells. Toxicol Sci, 72:84–91.
38.
FunatakeCJ, MarshallNB and KerkvlietNI. (2008). 2,3,7,8-Tetrachlorodibenzo-p-dioxin alters the differentiation of alloreactive CD8+ T cells toward a regulatory T cell phenotype by a mechanism that is dependent on aryl hydrocarbon receptor in CD4+ T cells. J Immunotoxicol, 5:81–91.
39.
VorderstrasseBA and KerkvlietNI. (2001). 2,3,7,8-Tetrachlorodibenzo-p-dioxin affects the number and function of murine splenic dendritic cells and their expression of accessory molecules. Toxicol Appl Pharmacol, 171:117–125.
40.
SinghKP, CasadoFL, OpanashukLA and GasiewiczTA. (2009). The aryl hydrocarbon receptor has a normal function in the regulation of hematopoietic and other stem/progenitor cell populations. Biochem Pharmacol, 77:577–587.
41.
RossiDJ, BryderD, ZahnJM, AhleniusH, SonuR, WagersAJ and WeissmanIL. (2005). Cell intrinsic alterations underlie hematopoietic stem cell aging. Proc Natl Acad Sci U S A, 102:9194–9199.
42.
SudoK, EmaH, MoritaY and NakauchiH. (2000). Age-associated characteristics of murine hematopoietic stem cells. J Exp Med, 192:1273–1280.
43.
LiangY, Van ZantG and SzilvassySJ. (2005). Effects of aging on the homing and engraftment of murine hematopoietic stem and progenitor cells. Blood, 106:1479–1487.
44.
LeeJ, YoonSR, ChoiI and JungH. (2019). Causes and mechanisms of hematopoietic stem cell aging. Int J Mol Sci, 20:1272.
45.
GeigerH, de HaanG and FlorianMC. (2013). The ageing haematopoietic stem cell compartment. Nat Rev Immunol, 13:376–389.
46.
AkunuruS and GeigerH. (2016). Aging, clonality, and rejuvenation of hematopoietic stem cells. Trends Mol Med, 22:701–712.
47.
LyM, RentasS, VujovicA, WongN, MoreiraS, XuJ, HolzapfelN, BhatiaS, TranD, et al. (2019). Diminished AHR signaling drives human acute myeloid leukemia stem cell maintenance. Cancer Res, 79:5799–5811.
48.
SinghKP, BennettJA, CasadoFL, WalrathJL, WelleSL and GasiewiczTA. (2014). Loss of aryl hydrocarbon receptor promotes gene changes associated with premature hematopoietic stem cell exhaustion and development of a myeloproliferative disorder in aging mice. Stem Cells Dev, 23:95–106.
49.
GentilM, HuguesP, DesterkeC, TelliamG, SlomaI, SouzaLEB, BaykalS, ArtusJ, GriscelliF, et al. (2018). Aryl hydrocarbon receptor (AHR) is a novel druggable pathway controlling malignant progenitor proliferation in chronic myeloid leukemia (CML). PLoS One, 13:e0200923.
50.
WagnerJEJr., BrunsteinCG, BoitanoAE, DeForTE, McKennaD, SumstadD, BlazarBR, TolarJ, LeC, et al. (2016). Phase I/II Trial of StemRegenin-1 expanded umbilical cord blood hematopoietic stem cells supports testing as a stand-alone graft. Cell Stem Cell, 18:144–155.
51.
StefanskiH, BrunsteinCG, McKennaDH, SumstadD, MillerJS, BlazarBR, DeForTE, BoitanoAE, CookeMP, et al. (2019). Mgta-456, an aryl hydrocarbon receptor (AHR) antagonist based expansion of CD34+ hematopoietic stem cells (HSC), permits selection of better HLA matched cord blood units (CBUs) and promotes faster neutrophil recovery and uniform engraftment with potentially less acute graft-vs-host disease (GVHD). Blood, 134:804.
52.
ThordardottirS, HangalapuraBN, HuttenT, CossuM, SpanholtzJ, SchaapN, RadstakeTR, van der VoortR and DolstraH. (2014). The aryl hydrocarbon receptor antagonist StemRegenin 1 promotes human plasmacytoid and myeloid dendritic cell development from CD34+ hematopoietic progenitor cells. Stem Cells Dev, 23:955–967.
53.
StrasselC, BrouardN, MalloL, ReceveurN, ManginP, EcklyA, BiecheI, TarteK, GachetC and LanzaF. (2016). Aryl hydrocarbon receptor-dependent enrichment of a megakaryocytic precursor with a high potential to produce proplatelets. Blood, 127:2231–2240.
54.
BoulaisPE and FrenettePS. (2015). Making sense of hematopoietic stem cell niches. Blood, 125:2621–2629.
55.
GilesAJ, ReidCM, EvansJD, MurgaiM, ViciosoY, HighfillSL, KasaiM, VahdatL, MackallCL, et al. (2016). Activation of hematopoietic stem/progenitor cells promotes immunosuppression within the pre-metastatic niche. Cancer Res, 76:1335–1347.
56.
WildesTJ, FloresCT and MitchellDA. (2019). Concise review: modulating cancer immunity with hematopoietic stem and progenitor cells. Stem Cells, 37:166–175.
Supplementary Material
Please find the following supplemental material available below.
For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.
For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.
