Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

M1 macrophage-derived exosomes transfer miR-222 to induce bone marrow mesenchymal stem cell apoptosis

Abstract

In the myocardial infarction microenvironment, the effect of macrophages on the function of bone marrow mesenchymal stem cells (BMSCs) is unclear. In this study, we investigated the role of hypoxia/serum deprivation (H/SD)-induced M1-type macrophage-derived exosomes on BMSC viability, migration, and apoptosis. We found that H/SD reduced BMSC viability and migration, increased BMSC apoptosis, and induced macrophage polarization toward the M1 phenotype. BMSCs were cultured by the supernatant of H/SD-induced THP-1 cells (M1-type macrophages) with or without exosome inhibitor treatment. The results show that BMSC apoptosis is increased in the H/SD-induced THP-1 cell supernatant group and is decreased by GM4869 treatment, indicating that M1-type macrophages induce BMSC apoptosis through exosomes. In addition, we confirm that miR-222 plays an important role in promoting BMSC apoptosis by targeting B-cell lymphoma (Bcl)-2. M1-type macrophage-derived exosomes significantly decrease BMSC viability and migration and increase BMSC apoptosis, and these effects are partly abolished by a miR-222 inhibitor. Our findings suggest that under H/SD conditions, exosomes derived from M1-type macrophages can induce BMSC apoptosis by delivering miR-222 to BMSCs.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Fig. 1: Hypoxia/serum deprivation (H/SD) induces BMSC apoptosis.
Fig. 2: H/SD induces macrophage polarization toward the M1 phenotype.
Fig. 3: Effects of M1-type macrophages on the viability, migration, and apoptosis of BMSCs.
Fig. 4: Effects of M1-type macrophage-derived exosomes on the viability, migration, and apoptosis of BMSCs.
Fig. 5: M1-type macrophages transport miR-222 through exosomes to affect the viability, migration, and apoptosis of BMSCs.
Fig. 6: M1 macrophage-derived exosomes deliver miR-222 to inhibit Bcl-2 protein expression and induce BMSC apoptosis.

Data availability

The datasets generated and/or analyzed during the current study are not publicly available but are available from the corresponding author on reasonable request.

References

  1. 1.

    Goedemans L, Bax J, Delgado V. COPD and acute myocardial infarction. Eur Respir Rev. 2020;29:190139.

    Article  Google Scholar 

  2. 2.

    Miao C, Lei M, Hu W, Han S, Wang Q. A brief review: the therapeutic potential of bone marrow mesenchymal stem cells in myocardial infarction. Stem Cell Res Ther. 2017;8:242.

    Article  Google Scholar 

  3. 3.

    Khodayari S, Khodayari H, Amiri A, Eslami M, Farhud D, Hescheler J, et al. Inflammatory microenvironment of acute myocardial infarction prevents regeneration of heart with stem cells therapy. Cell Physiol Biochem. 2019;53:887–909.

    CAS  Article  Google Scholar 

  4. 4.

    Hu M, Guo G, Huang Q, Cheng C, Xu R, Li A, et al. The harsh microenvironment in infarcted heart accelerates transplanted bone marrow mesenchymal stem cells injury: the role of injured cardiomyocytes-derived exosomes. Cell Death Dis. 2018;9:357.

    Article  Google Scholar 

  5. 5.

    Chen Y, Zuo J, Chen W, Yang Z, Zhang Y, Hua F, et al. The enhanced effect and underlying mechanisms of mesenchymal stem cells with IL-33 overexpression on myocardial infarction. Stem Cell Res Ther. 2019;10:295.

    Article  Google Scholar 

  6. 6.

    Zhou Y, Singh A, Hoyt R, Wang S, Yu Z, Hunt T, et al. Regulatory T cells enhance mesenchymal stem cell survival and proliferation following autologous cotransplantation in ischemic myocardium. J Thorac Cardiovasc Surg. 2014;148:1131–7.

    CAS  Article  Google Scholar 

  7. 7.

    Silva AM, Almeida MI, Teixeira JH, Maia AF, Calin GA, Barbosa MA, et al. Dendritic cell-derived extracellular vesicles mediate mesenchymal stem/stromal cell recruitment. Sci Rep. 2017;7:1667.

    Article  Google Scholar 

  8. 8.

    Ben-Mordechai T, Holbova R, Landa-Rouben N, Harel-Adar T, Feinberg M, Abd Elrahman I, et al. Macrophage subpopulations are essential for infarct repair with and without stem cell therapy. J Am Coll Cardiol. 2013;62:1890–901.

    Article  Google Scholar 

  9. 9.

    Cho DI, Kim MR, Jeong HY, Jeong HC, Jeong MH, Yoon SH, et al. Mesenchymal stem cells reciprocally regulate the M1/M2 balance in mouse bone marrow-derived macrophages. Exp Mol Med. 2014;46:e70.

    CAS  Article  Google Scholar 

  10. 10.

    Zhao J, Li X, Hu J, Chen F, Qiao S, Sun X, et al. Mesenchymal stromal cell-derived exosomes attenuate myocardial ischaemia-reperfusion injury through miR-182-regulated macrophage polarization. Cardiovasc Res. 2019;115:1205–16.

    CAS  Article  Google Scholar 

  11. 11.

    Hotchkiss KM, Clark NM, Olivares-Navarrete R. Macrophage response to hydrophilic biomaterials regulates MSC recruitment and T-helper cell populations. Biomaterials. 2018;182:202–15.

    CAS  Article  Google Scholar 

  12. 12.

    Mahon OR, Browe DC, Gonzalez-Fernandez T, Pitacco P, Whelan IT, Von Euw S, et al. Nano-particle mediated M2 macrophage polarization enhances bone formation and MSC osteogenesis in an IL-10 dependent manner. Biomaterials. 2020;239:119833.

    CAS  Article  Google Scholar 

  13. 13.

    Hessvik NP, Llorente A. Current knowledge on exosome biogenesis and release. Cell Mol Life Sci. 2018;75:193–208.

    CAS  Article  Google Scholar 

  14. 14.

    Yu X, Odenthal M, Fries JW. Exosomes as miRNA carriers: formation-function-future. Int J Mol Sci. 2016;17:2028.

    Article  Google Scholar 

  15. 15.

    Liu S, Chen J, Shi J, Zhou W, Wang L, Fang W, et al. M1-like macrophage-derived exosomes suppress angiogenesis and exacerbate cardiac dysfunction in a myocardial infarction microenvironment. Basic Res Cardiol. 2020;115:22.

    CAS  Article  Google Scholar 

  16. 16.

    Wang Z, Zhu H, Shi H, Zhao H, Gao R, Weng X, et al. Exosomes derived from M1 macrophages aggravate neointimal hyperplasia following carotid artery injuries in mice through miR-222/CDKN1B/CDKN1C pathway. Cell Death Dis. 2019;10:422.

    Article  Google Scholar 

  17. 17.

    Wang W, Wang J, Zhang J, Taq W, Zhang Z. miR‑222 induces apoptosis in human intervertebral disc nucleus pulposus cells by targeting Bcl‑2. Mol Med Rep. 2019;20:4875–82.

    CAS  PubMed  PubMed Central  Google Scholar 

  18. 18.

    Haddad K, Potter B, Matteau A, Reeves F, Leclerc G, Rivard A, et al. Analysis of the COMPARE-AMI trial: first report of long-term safety of CD133+ cells. Int J Cardiol. 2020;319:32–35.

    Article  Google Scholar 

  19. 19.

    Gong X, Fan G, Wang W, Wang G. Trimetazidine protects umbilical cord mesenchymal stem cells against hypoxia and serum deprivation induced apoptosis by activation of Akt. Cell Physiol Biochem. 2014;34:2245–55.

    CAS  Article  Google Scholar 

  20. 20.

    Wang F, Zhou H, Du Z, Chen X, Zhu F, Wang Z, et al. Cytoprotective effect of melatonin against hypoxia/serum deprivation-induced cell death of bone marrow mesenchymal stem cells in vitro. Eur J Pharmacol. 2015;748:157–65.

    CAS  Article  Google Scholar 

  21. 21.

    Liu W, Zhang X, Zhao M, Zhang X, Chi J, Liu Y, et al. Activation in M1 but not M2 macrophages contributes to cardiac remodeling after myocardial infarction in rats: a critical role of the calcium sensing receptor/NRLP3 inflammasome. Cell Physiol Biochem. 2015;35:2483–2500.

    CAS  Article  Google Scholar 

  22. 22.

    Ye L, He S, Mao X, Zhang Y, Cai Y, Li S. Effect of hepatic macrophage polarization and apoptosis on liver ischemia and reperfusion injury during liver transplantation. Front Immunol. 2020;11:1193.

    CAS  Article  Google Scholar 

  23. 23.

    Zhang F, Xuan Y, Cui J, Liu X, Shao Z, Yu B. Nicorandil modulated macrophages activation and polarization via NF-κb signaling pathway. Mol Immunol. 2017;88:69–78.

    CAS  Article  Google Scholar 

  24. 24.

    Chen L, Qiao P, Liu H, Shao L. Amorphous calcium phosphate NPs mediate the macrophage response and modulate BMSC osteogenesis. Inflammation. 2021;44:278–96.

    CAS  Article  Google Scholar 

  25. 25.

    Zhang J, Liu D, Zhang M, Zhang Y. Programmed necrosis in cardiomyocytes: mitochondria, death receptors and beyond. Br J Pharmacol.2019;176:4319–39.

    CAS  Article  Google Scholar 

Download references

Funding

This study was supported by National Nature Science Foundation of China (General Program; Grant number 81970312) and Natural Science Foundation of Henan Province (Grant number 182300410304).

Author information

Affiliations

Authors

Contributions

Y. Q. performed study concept and design; Y. Q., T. Z., T. Z., X. W., W. L., and D. C. performed development of methodology and writing, review, and revision of the paper; H. M. and S. A. provided acquisition, analysis and interpretation of data, and statistical analysis; H. M. provided technical and material support. All authors read and approved the final paper.

Corresponding author

Correspondence to Songtao An.

Ethics declarations

Conflict of interest

The authors declare no competing interests.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Qi, Y., Zhu, T., Zhang, T. et al. M1 macrophage-derived exosomes transfer miR-222 to induce bone marrow mesenchymal stem cell apoptosis. Lab Invest 101, 1318–1326 (2021). https://doi.org/10.1038/s41374-021-00622-5

Download citation

Search

Quick links