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Reduced regulatory effects of bone marrow-derived mesenchymal stem cells on activated T lymphocytes and Th1/Th2 cytokine secretion in children with aplastic anemia

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A Correction to this article was published on 06 December 2023

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Abstract

Acquired aplastic anemia (AA) is a recognized immune-mediated disorder and abnormally activated T lymphocyte-mediated bone marrow destruction is considered to be its main pathogenesis. Whether abnormal activation of T lymphocytes would also damage bone marrow-derived MSCs remains to be further studied. The aim of this study was to analyze the extent of T lymphocyte activation and the levels of Th1/Th2 cytokines of AA patients, and to explore the immunomodulatory effects of BM-MSCs on IL-2-stimulated T lymphocyte activation and cytokine production in vitro by means of transwell co-culture assay and flow cytometry measurement. The intermediate (CD25+) activated T cells were dominant in peripheral blood, while the early (CD69+) and late (HLA-DR+) activated T cells were predominant in bone marrow. Severe AA patients have an obviously higher proportion of CD3+CD8+CD69+ T cells than NSAA cases. The levels of IL-2 and IL-6 in AA patients were slightly elevated and INF-γ was mildly decreased in comparison with normal individuals. BM-MSCs derived from AA could not effectively inhibit the IL-2-induced activation of T cells with higher proportions of CD25+CD3+CD4+, CD69+CD3+CD4+ and CD25+CD3+CD8+ T cells after co-culture, and they showed a decreased ability to balance the Th1/Th2 cytokine production. Moreover, they had less robust osteogenic differentiation and more prone to adipogenic differentiation. We concluded that abnormally excessive T cell activation accompanied by abnormal cytokine secretion may impair the function of BM-MSCs in children with aplastic anemia.

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Data availability

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

Change history

Abbreviations

BM-MSCs:

Bone marrow-derived mesenchymal stem cells

AA:

Aplastic anemia

SAA:

Severe aplastic anemia

NSAA:

Non-severe aplastic anemia

PBMC:

Peripheral blood mononuclear cells

MACS:

Magnetic-activated cell sorting

References

  1. Young NS. Aplastic anemia. N Engl J Med. 2018;379:1643–56.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Schoettler ML, Nathan DG. The pathophysiology of acquired aplastic anemia: current concepts revisited. Hematol Oncol Clin N Am. 2018;32:581–94.

    Article  Google Scholar 

  3. Giudice V, Selleri C. Aplastic anemia: pathophysiology. Semin Hematol. 2022;59:13–20.

    Article  PubMed  Google Scholar 

  4. Liu J, Gao J, Liang Z, et al. Mesenchymal stem cells and their microenvironment. Stem Cell Res Ther. 2022;13:429.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Chao YH, Lin CW, Pan HH, et al. Increased apoptosis and peripheral blood mononuclear cell suppression of bone marrow mesenchymal stem cells in severe aplastic anemia. Pediatr Blood Cancer. 2018;65: e27247.

    Article  PubMed  Google Scholar 

  6. Huo J, Zhang L, Ren X, et al. Multifaceted characterization of the signatures and efficacy of mesenchymal stem/stromal cells in acquired aplastic anemia. Stem Cell Res Ther. 2020;11:59.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Wang XA, Li JP, Wu KH, et al. Mesenchymal stem cells in acquired aplastic anemia: the spectrum from basic to clinical utility. Int J Mol Sci. 2023;24:4464.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Li JP, Wu KH, Chao WR, et al. Alterations of mesenchymal stem cells on regulating Th17 and Treg differentiation in severe aplastic anemia. Aging (Albany NY). 2023;15:553–66.

    Article  CAS  PubMed  Google Scholar 

  9. Xing L, Liu C, Fu R, et al. CD8+HLA-DR+ T cells are increased in patients with severe aplastic anemia. Mol Med Rep. 2014;10:1252–8.

    Article  CAS  PubMed  Google Scholar 

  10. Kordasti S, Marsh J, Al-Khan S, et al. Functional characterization of CD4+ T cells in aplastic anemia. Blood. 2012;119:2033–43.

    Article  CAS  PubMed  Google Scholar 

  11. Javan MR, Saki N, Moghimian-Boroujeni B. Aplastic anemia, cellular and molecular aspects. Cell Biol Int. 2021;45:2395–402.

    Article  CAS  PubMed  Google Scholar 

  12. Guan J, Sun Y, Fu R, et al. A study of immune functionality of newly diagnosed severe aplastic anemia patients with virus infection. Clin Lab. 2019. https://doi.org/10.7754/clin.lab.2018.180905.

    Article  PubMed  Google Scholar 

  13. Red Blood Cell Disease (Anemia) Group. Chinese society of hematology, Chinese medical association. [Guidelines for the diagnosis and management of aplastic anemia in China (2022)]. Zhonghua Xue Ye Xue Za Zhi. 2022;43:881–8.

    Google Scholar 

  14. Guo X, Tang Y, Zhang P, et al. Effect of ectopic high expression of transcription factor OCT4 on the “stemness” characteristics of human bone marrow-derived mesenchymal stromal cells. Stem Cell Res Ther. 2019;10:160.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Tang Y, Xu X, Song H, et al. Early diagnostic and prognostic significance of a specific Th1/Th2 cytokine pattern in children with haemophagocytic syndrome. Br J Haematol. 2008;143:84–91.

    Article  CAS  PubMed  Google Scholar 

  16. Zhu C, Lian Y, Wang C, et al. Single-cell transcriptomics dissects hematopoietic cell destruction and T-cell engagement in aplastic anemia. Blood. 2021;138:23–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Zhao SS, Zhu XJ, Wu RH. Relationship between the changes of regulatory T cells and Th17 cells and the prognosis of children with aplastic anemia. Zhongguo Shi Yan Xue Ye Xue Za Zhi. 2020;28:1674–8 (Chinese).

    PubMed  Google Scholar 

  18. Fang J, Lin L, Wang Y, et al. Regulatory T cells and CD20+ B cells in pediatric very severe aplastic anemia: possible clinical markers for evaluating the therapeutic efficacy and prognosis. Hematology. 2018;23:823–7.

    Article  CAS  PubMed  Google Scholar 

  19. Shi J, Ge M, Lu S, et al. Intrinsic impairment of CD4(+)CD25(+) regulatory T cells in acquired aplastic anemia. Blood. 2012;120:1624–32.

    Article  CAS  PubMed  Google Scholar 

  20. Bacigalupo A, Valle M, Podestà M, et al. T-cell suppression mediated by mesenchymal stem cells is deficient in patients with severe aplastic anemia. Exp Hematol. 2005;33:819–27.

    Article  CAS  PubMed  Google Scholar 

  21. Raulf M. T cell: primary culture from peripheral blood. Methods Mol Biol. 2019;2020:17–31.

    Article  CAS  PubMed  Google Scholar 

  22. Sharma V, Kumar P, Kumar R, et al. Interferon-gamma and perforin-positive T cells in acquired aplastic anemia: implication in therapeutic response. Clin Exp Immunol. 2022;207:272–8.

    Article  PubMed  Google Scholar 

  23. Jiang BL, Li JP, Li WQ, Feng JM. Role of CD8(+)T cells and their secreted cytokines in the pathogenesis of aplastic anemia. Zhongguo Shi Yan Xue Ye Xue Za Zhi. 2014;22:569–72 (Chinese).

    CAS  PubMed  Google Scholar 

  24. Huang P, Zhang C, Delawary M, et al. Development and evaluation of IL-6 overexpressing mesenchymal stem cells (MSCs). J Tissue Eng Regen Med. 2022;16:244–53.

    Article  CAS  PubMed  Google Scholar 

  25. Philipp D, Suhr L, Wahlers T, et al. Preconditioning of bone marrow-derived mesenchymal stem cells highly strengthens their potential to promote IL-6-dependent M2b polarization. Stem Cell Res Ther. 2018;9:286.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We would like to thank Ping Chen and Ning Zhao in Hematology-Oncology Laboratory at Children’s Hospital of Zhejiang University School of Medicine for their excellent FCM technical support.

Funding

This work was supported by the grant from Natural Science Foundation of Zhejiang Province (No: LY20H080007).

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Authors and Affiliations

  1. Department/Center of Pediatric Hematology-Oncology, Children’s Hospital of Zhejiang University School of Medicine, National Clinical Research Center for Child Health, #57 Zhuganxiang Road, Yan-an Street, Hangzhou, 310003, People’s Republic of China

    Xiaoping Guo, Wenwen Weng, Yuwen Wang, Yuanyuan Chen, Hua Song, Jingying Zhang, Weiqun Xu, Xiaojun Xu & Yongmin Tang

  2. Department of Non-communicable Disease Prevention, Zhejiang Provincial Center for Disease Control and Prevention, 3399 Binsheng Road, Binjiang District, Hangzhou City, 310051, Zhejiang Province, People’s Republic of China

    Jin Pan

  3. School of Medicine, Zhejiang University City College, #51 Huzhou Street, Hangzhou, 310015, People’s Republic of China

    Sisi Li

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  1. Xiaoping Guo
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  2. Wenwen Weng
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Contributions

XP G conceived, designed and carried out the study, and drafted the manuscript. WW W and YW W carried out part of the study, JP performed the statistical analysis. SS L performed the FCM data analysis. HS, JY Z and WQ X provided the technical assistance in disease diagnosis and clinical data analysis. YC collected and aggregated part of the clinical data. XJ X and YM T participated in the design of the study and helped to draft and edit the manuscript. All authors read and approved the final version of the manuscript.

Corresponding authors

Correspondence to Xiaojun Xu or Yongmin Tang.

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Conflict of interest

The authors declare no conflict of competing interests.

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Not applicable.

Ethics approval and consent to participate

This study was performed in line with the principles of the Declaration of Helsinki. The informed consents were obtained from the parents or guardians, and the ethics approval was required according to the guidelines on the Use of Human Subjects in Research. All the procedures described in this report have been approved by the Ethics Committee of Children’s Hospital of Zhejiang University School (Approval number: 2021-IRBAL-045; Approval date: 2021-02-09).

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The original online version of this article was revised due to a retrospective Open Access cancellation.

Supplementary Information

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10238_2023_1238_MOESM1_ESM.jpg

Fig. 5 (Supplementary) Morphology of P3 BM-MSCs and their osteogenic and adipogenic differentiation in bright field. Left image is the fibroblast-like morphology of BM-MSCs from patients with AA and control individuals at P3. Osteogenic and adipogenic differentiation of BM-MSCs in bright field. Right image is relative expression of osteogenic and adipogenic differentiation related genes (ALPL and PPAR-γ) by qRT-PCR to confirm the RNA-Seq results (DATA unpublished, not shown) (JPG 1183 KB)

Supplementary file2 (DOCX 16 KB)

Supplementary file3 (DOCX 13 KB)

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Guo, X., Weng, W., Wang, Y. et al. Reduced regulatory effects of bone marrow-derived mesenchymal stem cells on activated T lymphocytes and Th1/Th2 cytokine secretion in children with aplastic anemia. Clin Exp Med 23, 4633–4646 (2023). https://doi.org/10.1007/s10238-023-01238-3

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