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Indole-3-carboxaldehyde ameliorates ionizing radiation-induced hematopoietic injury by enhancing hematopoietic stem and progenitor cell quiescence

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Abstract

Indole-3-carboxaldehyde (I3A), one of tryptophan metabolites derived from gut microbiota, extends the lifespan of mice after high-dose ionizing radiation exposure. Persistent myelosuppression is the most common and fatal complication for victims of nuclear accidents and patients undergoing radiotherapy, with few therapeutic options available. However, whether and how I3A protects ionizing radiation-induced hematopoietic toxicity remain unknown. In this study, we demonstrated that I3A treatment effectively ameliorated radiation-induced hematopoietic injury through accelerating peripheral blood cells recovery, promoting bone marrow cellularity restoration and enhancing functional HSPC regeneration. Additionally, I3A also suppressed intracellular reactive oxygen species production and inhibited apoptosis in irradiated HSPCs. Mechanistically, I3A treatment significantly increased HSPC quiescence, thus conferring HSPCs with resistance against radiation injury. Finally, I3A treatment could improve survival of lethally irradiated mice. Taken together, our data suggest that I3A acts as a gut microbiota-derived paracrine factor that regulates HSPC regeneration and may serve as a promising therapeutic agent for ionizing radiation-induced myelosuppression.

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Data availability

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Abbreviations

I3A:

Indole-3-carboxaldehyde

HSPCs:

Hematopoietic stem and progenitor cells

HSCs:

Hematopoietic stem cells

IR:

Ionizing radiation

MPP:

Multipotent progenitor

AhR:

Aryl hydrocarbon receptor

DMSO:

Dimethyl sulfoxide

BM:

Bone marrow

PB:

Peripheral blood

LSK:

Lin−Sca1+cKit+

ROS:

Reactive oxygen species

qRT-PCR:

Quantitative real-time polymerase chain reaction

ANOVA:

One-way analysis of variance

SD:

Standard deviation

MP:

Myeloid progenitor

LT-HSCs:

Long-term HSCs

ST-HSCs:

Short-term HSCs

WBC:

White blood cells

Lym:

Lymphocytes

Neu:

Neutrophils

RBC:

Red blood cells

HGB:

Hemoglobin

PLT:

Platelets

References

  1. Zsebo KM, Smith KA, Hartley CA, Greenblatt M, Cooke K, Rich W et al (1992) Radioprotection of mice by recombinant rat stem cell factor. Proc Natl Acad Sci USA 89:9464–9468. https://doi.org/10.1073/pnas.89.20.9464

    Article  CAS  PubMed  PubMed Central  ADS  Google Scholar 

  2. Doan PL, Himburg HA, Helms K, Russell JL, Fixsen E, Quarmyne M et al (2013) Epidermal growth factor regulates hematopoietic regeneration after radiation injury. Nat Med 19:295–304. https://doi.org/10.1038/nm.3070

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Himburg HA, Yan X, Doan PL, Quarmyne M, Micewicz E, McBride W et al (2014) Pleiotrophin mediates hematopoietic regeneration via activation of RAS. J Clin Invest 124:4753–4758. https://doi.org/10.1172/JCI76838

    Article  PubMed  PubMed Central  Google Scholar 

  4. Himburg HA, Doan PL, Quarmyne M, Yan X, Sasine J, Zhao L et al (2017) Dickkopf-1 promotes hematopoietic regeneration via direct and niche-mediated mechanisms. Nat Med 23:91–99. https://doi.org/10.1038/nm.4251

    Article  CAS  PubMed  Google Scholar 

  5. Goncalves KA, Silberstein L, Li S, Severe N, Hu MG, Yang H et al (2016) Angiogenin promotes hematopoietic regeneration by dichotomously regulating quiescence of stem and progenitor cells. Cell 166:894–906. https://doi.org/10.1016/j.cell.2016.06.042

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Chapple RH, Hu T, Tseng YJ, Liu L, Kitano A, Luu V et al (2018) ERalpha promotes murine hematopoietic regeneration through the Ire1alpha-mediated unfolded protein response. Elife 7:e31159. https://doi.org/10.7554/eLife.31159

    Article  PubMed  PubMed Central  Google Scholar 

  7. Yan H (2018) Hematopoiesis and the bacterial microbiome. Blood 132:559–564. https://doi.org/10.1182/blood-2018-02-832519

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Iwamura C, Bouladoux N, Belkaid Y (2017) Sensing of the microbiota by NOD1 in mesenchymal stromal cells regulates murine hematopoiesis. Blood 129:171–176. https://doi.org/10.1182/blood-2016-06-723742

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Balmer ML, Schurch CM, Saito Y, Geuking MB, Li H, Cuenca M et al (2014) Microbiota-derived compounds drive steady-state granulopoiesis via MyD88/TICAM signaling. J Immunol 193:5273–5283. https://doi.org/10.4049/jimmunol.1400762

    Article  CAS  PubMed  Google Scholar 

  10. Khosravi A, Yanez A, Price JG, Chow A, Merad M, Goodridge HS et al (2014) Gut microbiota promote hematopoiesis to control bacterial infection. Cell Host Microbe 15:374–381. https://doi.org/10.1016/j.chom.2014.02.006

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Josefsdottir KS, Baldridge MT (2017) Antibiotics impair murine hematopoiesis by depleting the intestinal microbiota. Blood 129:729–739. https://doi.org/10.1182/blood-2016-03-708594

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Yan H, Walker FC, Ali A, Han H, Tan L, Veillon L et al (2022) The bacterial microbiota regulates normal hematopoiesis via metabolite-induced type 1 interferon signaling. Blood Adv 6:1754–1765. https://doi.org/10.1182/bloodadvances.2021006816

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Crawford JI (2005) Microbial regulation of intestinal radiosensitivity. Proc Natl Acad Sci USA 102:13254–13259. https://doi.org/10.1073/pnas.0504830102

    Article  CAS  PubMed  PubMed Central  ADS  Google Scholar 

  14. Cui M, Xiao H, Li Y, Zhou L, Zhao S, Luo D et al (2017) Faecal microbiota transplantation protects against radiation-induced toxicity. EMBO Mol Med 9:448–461. https://doi.org/10.15252/emmm.201606932

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Xiao HW, Cui M, Li Y, Dong JL, Zhang SQ, Zhu CC et al (2020) Gut microbiota-derived indole 3-propionic acid protects against radiation toxicity via retaining acyl-CoA-binding protein. Microbiome 8:69. https://doi.org/10.1186/s40168-020-00845-6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Guo H, Chou WC, Lai Y, Liang K, Tam JW, Brickey WJ et al (2020) Multi-omics analyses of radiation survivors identify radioprotective microbes and metabolites. Science. https://doi.org/10.1126/science.aay9097

    Article  PubMed  PubMed Central  Google Scholar 

  17. Zelante T, Iannitti RG, Cunha C, De Luca A, Giovannini G, Pieraccini G et al (2013) Tryptophan catabolites from microbiota engage aryl hydrocarbon receptor and balance mucosal reactivity via interleukin-22. Immunity 39:372–385. https://doi.org/10.1016/j.immuni.2013.08.003

    Article  CAS  PubMed  Google Scholar 

  18. Powell DN, Swimm A, Sonowal R, Bretin A, Gewirtz AT, Jones RM et al (2020) Indoles from the commensal microbiota act via the AHR and IL-10 to tune the cellular composition of the colonic epithelium during aging. Proc Natl Acad Sci USA 117:21519–21526. https://doi.org/10.1073/pnas.2003004117

    Article  CAS  PubMed  PubMed Central  ADS  Google Scholar 

  19. Peng R, Zhang W, Zuo Z, Shan Y, Liu X, Tang Y et al (2020) Dimethyl sulfoxide, a potent oral radioprotective agent, confers radioprotection of hematopoietic stem and progenitor cells independent of apoptosis. Free Radic Biol Med 153:1–11. https://doi.org/10.1016/j.freeradbiomed.2020.03.021

    Article  CAS  PubMed  Google Scholar 

  20. Qi Y, Chen S, Lu Y, Zhang Z, Wang S, Chen N et al (2021) Grape seed proanthocyanidin extract ameliorates ionizing radiation-induced hematopoietic stem progenitor cell injury by regulating Foxo1 in mice. Free Radic Biol Med 174:144–156. https://doi.org/10.1016/j.freeradbiomed.2021.08.010

    Article  CAS  PubMed  Google Scholar 

  21. Johnson SM, Torrice CD, Bell JF, Monahan KB, Jiang Q, Wang Y et al (2010) Mitigation of hematologic radiation toxicity in mice through pharmacological quiescence induced by CDK4/6 inhibition. J Clin Invest 120:2528–2536. https://doi.org/10.1172/JCI41402

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. He S, Roberts PJ, Sorrentino JA, Bisi JE, Storrie-White H, Tiessen RG et al (2017) Transient CDK4/6 inhibition protects hematopoietic stem cells from chemotherapy-induced exhaustion. Sci Transl Med. https://doi.org/10.1126/scitranslmed.aal3986

    Article  PubMed  PubMed Central  Google Scholar 

  23. Winkler IG, Barbier V, Nowlan B, Jacobsen RN, Forristal CE, Patton JT et al (2012) Vascular niche E-selectin regulates hematopoietic stem cell dormancy, self renewal and chemoresistance. Nat Med 18:1651–1657. https://doi.org/10.1038/nm.2969

    Article  CAS  PubMed  Google Scholar 

  24. Velardi E, Tsai JJ, Radtke S, Cooper K, Argyropoulos KV, Jae-Hung S et al (2018) Suppression of luteinizing hormone enhances HSC recovery after hematopoietic injury. Nat Med 24:239–246. https://doi.org/10.1038/nm.4470

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Patterson AM, Liu L, Sampson CH, Plett PA, Li H, Singh P et al (2020) A single radioprotective dose of prostaglandin E2 blocks irradiation-induced apoptotic signaling and early cycling of hematopoietic stem cells. Stem Cell Reports 15:358–373. https://doi.org/10.1016/j.stemcr.2020.07.004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Rodrigues-Moreira S, Moreno SG, Ghinatti G, Lewandowski D, Hoffschir F, Ferri F et al (2017) Low-dose irradiation promotes persistent oxidative stress and decreases self-renewal in hematopoietic stem cells. Cell Rep 20:3199–3211. https://doi.org/10.1016/j.celrep.2017.09.013

    Article  CAS  PubMed  Google Scholar 

  27. Renga G, Nunzi E, Pariano M, Puccetti M, Bellet MM, Pieraccini G et al (2022) Optimizing therapeutic outcomes of immune checkpoint blockade by a microbial tryptophan metabolite. J Immunother Cancer 10:e003725. https://doi.org/10.1136/jitc-2021-003725

    Article  PubMed  PubMed Central  Google Scholar 

  28. Zhang R, Huang G, Ren Y, Wang H, Ye Y, Guo J et al (2022) Effects of dietary indole-3-carboxaldehyde supplementation on growth performance, intestinal epithelial function, and intestinal microbial composition in weaned piglets. Front Nutr 9:896815. https://doi.org/10.3389/fnut.2022.896815

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Kumar A, Patel VS, Harding JN (2021) Exposure to combustion derived particulate matter exacerbates influenza infection in neonatal mice by inhibiting IL22 production. Part Fibre Toxicol 18:43. https://doi.org/10.1186/s12989-021-00438-7

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Puccetti M, Pariano M, Borghi M, Barola C, Moretti S, Galarini R et al (2021) Enteric formulated indole-3-carboxaldehyde targets the aryl hydrocarbon receptor for protection in a murine model of metabolic syndrome. Int J Pharm 602:120610. https://doi.org/10.1016/j.ijpharm.2021.120610

    Article  CAS  PubMed  Google Scholar 

  31. Naseri-Nosar P (2021) The aryl hydrocarbon receptor facilitates the human cytomegalovirus-mediated G1/S block to cell cycle progression. Proc Natl Acad Sci USA 118:e2026336118. https://doi.org/10.1073/pnas.2026336118

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Wei GZ, Martin KA, Xing PY, Agrawal R, Whiley L, Wood TK et al (2021) Tryptophan-metabolizing gut microbes regulate adult neurogenesis via the aryl hydrocarbon receptor. Proc Natl Acad Sci USA 118:e2021091118. https://doi.org/10.1073/pnas.2021091118

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Krishnan S, Ding Y, Saedi N, Choi M, Sridharan GV, Sherr DH et al (2018) Gut microbiota-derived tryptophan metabolites modulate inflammatory response in hepatocytes and macrophages. Cell Rep 23:1099–1111. https://doi.org/10.1016/j.celrep.2018.03.109

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Rothhammer V, Mascanfroni ID, Bunse L, Takenaka MC, Kenison JE, Mayo L et al (2016) Type I interferons and microbial metabolites of tryptophan modulate astrocyte activity and central nervous system inflammation via the aryl hydrocarbon receptor. Nat Med 22:586–597. https://doi.org/10.1038/nm.4106

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Liu X, Zhang X, Zhang J, Luo Y, Xu B, Ling S et al (2020) Activation of aryl hydrocarbon receptor in Langerhans cells by a microbial metabolite of tryptophan negatively regulates skin inflammation. J Dermatol Sci 100:192–200. https://doi.org/10.1016/j.jdermsci.2020.10.004

    Article  CAS  PubMed  Google Scholar 

  36. Singh KP, Casado FL (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. https://doi.org/10.1016/j.bcp.2008.10.001

    Article  CAS  PubMed  Google Scholar 

  37. Singh KP, Wyman A, Casado FL (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. https://doi.org/10.1093/carcin/bgn224

    Article  CAS  PubMed  Google Scholar 

  38. Singh KP, Garrett RW (2011) Aryl hydrocarbon receptor-null allele mice have hematopoietic stem/progenitor cells with abnormal characteristics and functions. Stem Cells Dev 20:769–784. https://doi.org/10.1089/scd.2010.0333

    Article  CAS  PubMed  Google Scholar 

  39. Singh KP, Bennett JA, Casado FL, Walrath JL (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. https://doi.org/10.1089/scd.2013.0346

    Article  CAS  PubMed  Google Scholar 

  40. Boitano AE, Wang J, Romeo R, Bouchez LC, Parker AE, Sutton SE et al (2010) Aryl hydrocarbon receptor antagonists promote the expansion of human hematopoietic stem cells. Science 329:1345–1348. https://doi.org/10.1126/science.1191536

    Article  CAS  PubMed  PubMed Central  ADS  Google Scholar 

  41. Wagner JE Jr, Brunstein CG, Boitano AE, DeFor TE, McKenna D, Sumstad D 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. https://doi.org/10.1016/j.stem.2015.10.004

    Article  CAS  PubMed  Google Scholar 

  42. Bogeska R, Mikecin AM, Kaschutnig P, Fawaz M, Buchler-Schaff M, Le D et al (2022) Inflammatory exposure drives long-lived impairment of hematopoietic stem cell self-renewal activity and accelerated aging. Cell Stem Cell 29:1273–1284. https://doi.org/10.1016/j.stem.2022.06.012

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Yahyapour R, Amini P, Rezapoor S, Rezaeyan A, Farhood B, Cheki M et al (2018) Targeting of inflammation for radiation protection and mitigation. Curr Mol Pharmacol 11:203–210. https://doi.org/10.2174/1874467210666171108165641

    Article  CAS  PubMed  Google Scholar 

  44. Bansal T, Alaniz RC (2010) The bacterial signal indole increases epithelial-cell tight-junction resistance and attenuates indicators of inflammation. Proc Natl Acad Sci USA 107:228–233. https://doi.org/10.1073/pnas.0906112107

    Article  PubMed  ADS  Google Scholar 

  45. Wlodarska M, Luo C, Kolde R, d’Hennezel E, Annand JW, Heim CE et al (2017) Indoleacrylic acid produced by commensal Peptostreptococcus species suppresses inflammation. Cell Host Microbe 22:25–37. https://doi.org/10.1016/j.chom.2017.06.007

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Borghi M, Pariano M, Solito V, Puccetti M, Bellet MM, Stincardini C et al (2019) Targeting the aryl hydrocarbon receptor with indole-3-aldehyde protects from vulvovaginal candidiasis via the IL-22-IL-18 cross-talk. Front Immunol 10:2364. https://doi.org/10.3389/fimmu.2019.02364

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We would like to thank Yu Hou (Department of Hematology, Southwest Hospital, Army Military Medical University, Chongqing, China) for the gift of congenic CD45.1 mice.

Funding

This work was supported by Natural Science Foundation of China (No. 81170471, No. 31371393), the Intramural Research Project Grants (No. AWS17J007), Fundamental Research Funds for the Central Universities (No. 2021CDJYGRH-003), and China Postdoctoral Science Foundation (No. 2021M700598).

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Author notes

  1. Dongwei Guan and Yonghao Yang have equally contributed to this work and should be considered co-first authors.

Authors and Affiliations

  1. Laboratary Animal Research Center, School of Medicine, Chongqing University, Chongqing, 400044, China

    Dongwei Guan, Yonghao Yang, Mao Pang, Xinlei Liu, Yang Li, Pengju Huang & Zhijia Ye

  2. Stem Cell Research Center, School of Medicine, Chongqing University, Chongqing, 400044, China

    Dongwei Guan, Yonghao Yang, Mao Pang, Xinlei Liu, Yang Li, Pengju Huang & Zhijia Ye

  3. Institute of Precision Medicine, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, 510080, China

    Haitao Shang

  4. Jinfeng Laboratory, Chongqing, 401329, China

    Hong Wei

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  1. Dongwei Guan
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Contributions

DG, YY and ZY conceived and designed the project. DG, YY, MP, XL, YL and PH performed the experiments and analyzed the data. HS and HW assisted with animal experiments. DG and YY drafted the manuscript. ZY provided funding support and revised the manuscript. All authors have read and approved the final manuscript.

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Correspondence to Dongwei Guan or Zhijia Ye.

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The authors declare that they have no competing interests.

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This study was approved by the institutional animal care and use committee of Chongqing University (Approval No. CQU-IACUC-RE-202211-003).

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Guan, D., Yang, Y., Pang, M. et al. Indole-3-carboxaldehyde ameliorates ionizing radiation-induced hematopoietic injury by enhancing hematopoietic stem and progenitor cell quiescence. Mol Cell Biochem 479, 313–323 (2024). https://doi.org/10.1007/s11010-023-04732-0

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