Skip to main content

Advertisement

SpringerLink
Log in

Mesenchymal stem cells suppressed skin and lung inflammation and fibrosis in topoisomerase I-induced systemic sclerosis associated with lung disease mouse model

  • Regular Article
  • Published:
Cell and Tissue Research Aims and scope Submit manuscript

Abstract

Systemic sclerosis associated with lung interstitial lung disease (SSc-ILD) is the most common cause of death among patients with SSc. Mesenchymal stem cell (MSCs) transplantations had been treated by SSc patients that showed in the previous case report. The therapeutic mechanisms and effects of MSCs on SSc-ILD are still obscure. In this study, we investigated the therapeutic effects and mechanisms of treatment of BM-MSC derived from C57BL/6 on the topoisomerase I (TOPO I) induced SSc-ILD-like mice model. The mice were immunized with a mixture of recombinant human TOPO I in PBS solution (500 U/mL) and completed Freund’s adjuvant [CFA; 1:1 (volume/volume)] twice per week for 9 weeks. On week 10, the mice were sacrificed to analyze the related pathological parameters. Lung and skin pathologies were analyzed using histochemical staining. CD4 T-helper (TH) cell differentiation in lung and skin-draining lymph nodes was detected using flow cytometry. Our results revealed that allogeneic and syngeneic MSCs exhibited similar repressive effects on TOPO I-induced IgG1 and IgG2a in the SSc group. After intravascular (IV) treatment with syngeneic or allogeneic MSCs, the dermal thickness and fibrosis dramatically condensed and significantly reduced airway hyperresponsiveness. These findings showed that both allogeneic and syngeneic MSCs have therapeutic potential for SSc-ILD.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9
Fig. 10

Similar content being viewed by others

References

  • Boonstra M, Bakker JA, Grummels A, Ninaber MK, Marsan NA, Wortel CM, Huizinga TWJ, Jordan S, Hoffman-Vold AM, Distler O, Toes REM, Scherer HU, de Vries-Bouwstra JK (2020) Association of anti-topoisomerase I antibodies of the IgM isotype with disease progression in anti-topoisomerase I-positive systemic sclerosis. Arthritis Rheumatol 72:1897–1904

    Article  CAS  Google Scholar 

  • Brembilla NC, Montanari E, Truchetet ME, Raschi E, Meroni P, Chizzolini C (2013) Th17 cells favor inflammatory responses while inhibiting type I collagen deposition by dermal fibroblasts: differential effects in healthy and systemic sclerosis fibroblasts. Arthritis Res Ther 15(5)

  • Chang YD, Li CH, Tsai CH, Cheng YW, Kang JJ, Lee CC (2020) Aryl hydrocarbon receptor deficiency enhanced airway inflammation and remodeling in a murine chronic asthma model. Faseb J 34:15300–15313

    Article  CAS  Google Scholar 

  • Chizzolini C, Parel Y, Scheja A, Dayer JM (2006) Polarized subsets of human T-helper cells induce distinct patterns of chemokine production by normal and systemic sclerosis dermal fibroblasts. Arthritis Res Ther 8:R10

    Article  Google Scholar 

  • Cipriani P, Di Benedetto P, Liakouli V, Del Papa B, Di Padova M, Di Ianni M, Marrelli A, Alesse E, Giacomelli R (2013) Mesenchymal stem cells (MSCs) from scleroderma patients (SSc) preserve their immunomodulatory properties although senescent and normally induce T regulatory cells (Tregs) with a functional phenotype: implications for cellular-based therapy. Clin Exp Immunol 173:195–206

    Article  CAS  Google Scholar 

  • Di Nicola M, Carlo-Stella C, Magni M, Milanesi M, Longoni PD, Matteucci P, Grisanti S, Gianni AM (2002) Human bone marrow stromal cells suppress T-lymphocyte proliferation induced by cellular or nonspecific mitogenic stimuli. Blood 99:3838–3843

    Article  Google Scholar 

  • Dominici M, Le Blanc K, Mueller I, Slaper-Cortenbach I, Marini FC, Krause DS, Deans RJ, Keating A, Prockop DJ, Horwitz EM (2006) Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy 8:315–317

    Article  CAS  Google Scholar 

  • Fan Y, Bender S, Shi W, Zoz D (2020) Incidence and prevalence of systemic sclerosis and systemic sclerosis with interstitial lung disease in the United States. J Manag Care Spec Pharm 26:1539–1547

    Google Scholar 

  • Fuschiotti P (2016) Current perspectives on the immunopathogenesis of systemic sclerosis. Immunotargets Ther 5:21–35

    Article  CAS  Google Scholar 

  • Goh NS, Desai SR, Veeraraghavan S, Hansell DM, Copley SJ, Maher TM, Corte TJ, Sander CR, Ratoff J, Devaraj A, Bozovic G, Denton CP, Black CM, du Bois RM, Wells AU (2008) Interstitial lung disease in systemic sclerosis: a simple staging system. Am J Respir Crit Care Med 177:1248–1254

    Article  Google Scholar 

  • Hamelmann E, Schwarze J, Takeda K, Oshiba A, Larsen GL, Irvin CG, Gelfand EW (1997) Noninvasive measurement of airway responsiveness in allergic mice using barometric plethysmography. Am J Resp Crit Care 156:766–775

    Article  CAS  Google Scholar 

  • Hénault J, Tremblay M, Clément I, Raymond Y, Senécal JL (2004) Direct binding of anti-DNA topoisomerase I autoantibodies to the cell surface of fibroblasts in patients with systemic sclerosis. Arthritis Rheum 50:3265–3274

    Article  Google Scholar 

  • Jacobs SA, Roobrouck VD, Verfaillie CM, Van Gool SW (2013) Immunological characteristics of human mesenchymal stem cells and multipotent adult progenitor cells. Immunol Cell Biol 91:32–39

    Article  CAS  Google Scholar 

  • Koenig M, Joyal F, Fritzler MJ, Roussin A, Abrahamowicz M, Boire G, Goulet JR, Rich E, Grodzicky T, Raymond Y, Senécal JL (2008) Autoantibodies and microvascular damage are independent predictive factors for the progression of Raynaud’s phenomenon to systemic sclerosis: a twenty-year prospective study of 586 patients, with validation of proposed criteria for early systemic sclerosis. Arthritis Rheum 58:3902–3912

    Article  Google Scholar 

  • Kumamoto M, Nishiwaki T, Matsuo N, Kimura H, Matsushima K (2009) Minimally cultured bone marrow mesenchymal stem cells ameliorate fibrotic lung injury. Eur Respir J 34:740–748

    Article  CAS  Google Scholar 

  • Kuwana M, Kaburaki J, Mimori T, Kawakami Y, Tojo T (2000) Longitudinal analysis of autoantibody response to topoisomerase I in systemic sclerosis. Arthritis Rheum-Us 43:1074–1084

    Article  CAS  Google Scholar 

  • Le Blanc K, Frassoni F, Ball L, Locatelli F, Roelofs H, Lewis I, Lanino E, Sundberg B, Bernardo ME, Remberger M, Dini G, Egeler RM, Bacigalupo A, Fibbe W, Ringden O, Developmental Committee of the European Group for B, Marrow T (2008) Mesenchymal stem cells for treatment of steroid-resistant, severe, acute graft-versus-host disease: a phase II study. Lancet 371:1579–1586

    Article  Google Scholar 

  • Lee CC, Lin CL, Leu SJ, Lee YL (2018a) Overexpression of Notch ligand Delta-like-1 by dendritic cells enhances their immunoregulatory capacity and exerts antiallergic effects on Th2-mediated allergic asthma in mice. Clin Immunol 187:58–67

    Article  CAS  Google Scholar 

  • Lee K, Park N, Jung H, Rim YA, Nam Y, Lee J, Park SH, Ju H (2018b) Mesenchymal stem cells ameliorate experimental arthritis via expression of interleukin-1 receptor antagonist. Plos One 13(2)

  • Lee SH, Jang AS, Kim YE, Cha JY, Kim TH, Jung S, Park SK, Lee YK, Won JH, Kim YH, Park CS (2010) Modulation of cytokine and nitric oxide by mesenchymal stem cell transfer in lung injury/fibrosis. Resp Res 11

  • Lee YL, Chang YD, Liu CW, Lee CC (2020) Extract of Pyrus nivalis enhances phagocytosis in lungs after particles matter exposure in BALB/c mice. J Food Biochem e13469

  • Lei L, Zhao C, Qin F, He ZY, Wang X, Zhong XN (2016) Th17 cells and IL-17 promote the skin and lung inflammation and fibrosis process in a bleomycin-induced murine model of systemic sclerosis. Clin Exp Rheumatol 34:S14–S22

    Google Scholar 

  • Machado CV, Telles PD, Nascimento IL (2013) Immunological characteristics of mesenchymal stem cells. Rev Bras Hematol Hemoter 35(1):62–67

    Article  Google Scholar 

  • Maria ATJ, Maumus M, Le Quellec A, Jorgensen C, Noel D, Guilpain P (2017) Adipose-derived mesenchymal stem cells in autoimmune disorders: state of the art and perspectives for systemic sclerosis. Clin Rev Allerg Immu 52:234–259

    Article  CAS  Google Scholar 

  • Maria ATJ, Toupet K, Bony C, Pirot N, Vozenin MC, Petit B, Roger P, Batteux F, Le Quellec A, Jorgensen C, Noel D, Guilpain P (2016) Antifibrotic, antioxidant, and immunomodulatory effects of mesenchymal stem cells in HOCl-induced systemic sclerosis. Arthritis Rheumatol 68:1013–1025

    Article  CAS  Google Scholar 

  • Maria ATJ, Toupet K, Maumus M, Rozier P, Vozenin MC, Le Quellec A, Jorgensen C, Noel D, Guilpain P (2018) Fibrosis development in HOCl-induced systemic sclerosis: a multistage process hampered by mesenchymal stem cells. Front Immunol 9:2571

    Article  Google Scholar 

  • Martinet L, Fleury-Cappellesso S, Gadelorge M, Dietrich G, Bourin P, Fournié JJ, Poupot R (2009) A regulatory cross-talk between Vgamma9Vdelta2 T lymphocytes and mesenchymal stem cells. Eur J Immunol 39:752–762

    Article  CAS  Google Scholar 

  • Maumus M, Guerit D, Toupet K, Jorgensen C, Noel D (2011) Mesenchymal stem cell-based therapies in regenerative medicine: applications in rheumatology. Stem Cell Res Ther 2:14

    Article  Google Scholar 

  • Mehta H, Goulet PO, Nguyen V, Perez G, Koenig M, Senecal JL, Sarfati M (2016) Topoisomerase I peptide-loaded dendritic cells induce autoantibody response as well as skin and lung fibrosis. Autoimmunity 49:503–513

    Article  CAS  Google Scholar 

  • Meyer KC (2018) Scleroderma with fibrosing interstitial lung disease: where do we stand? Ann Am Thorac Soc 15:1273–1275

    Article  Google Scholar 

  • Nemeth K, Leelahavanichkul A, Yuen PST, Mayer B, Parmelee A, Doi K, Robey PG, Leelahavanichkul K, Koller BH, Brown JM, Hu XZ, Jelinek I, Star RA, Mezey E (2009) Bone marrow stromal cells attenuate sepsis via prostaglandin E-2-dependent reprogramming of host macrophages to increase their interleukin-10 production. Nature Medicine 15:42–49

  • Ortiz LA, Gambelli F, McBride C, Gaupp D, Baddoo M, Kaminski N, Phinney DG (2003) Mesenchymal stem cell engraftment in lung is enhanced in response to bleomycin exposure and ameliorates its fibrotic effects. P Natl Acad Sci USA 100:8407–8411

    Article  CAS  Google Scholar 

  • Reveille JD, Solomon DH (2003) Evidence-based guidelines for the use of immunologic tests: anticentromere, Scl-70, and nucleolar antibodies. Arthritis Rheum 49:399–412

    Article  Google Scholar 

  • Rojas M, Xu JG, Woods CR, Mora AL, Spears W, Roman J, Brigham KL (2005) Bone marrow-derived mesenchymal stem cells in repair of the injured lung. Am J Resp Cell Mol 33:145–152

    Article  CAS  Google Scholar 

  • Rozier P, Maria A, Goulabchand R, Jorgensen C, Guilpain P, Noel D (2018) Mesenchymal stem cells in systemic sclerosis: allogenic or autologous approaches for Therapeutic ase? Front Immunol 9:2938

    Article  CAS  Google Scholar 

  • Senécal JL, Hénault J, Raymond Y (2005) The pathogenic role of autoantibodies to nuclear autoantigens in systemic sclerosis (scleroderma). J Rheumatol 32:1643–1649

    Google Scholar 

  • Shackelford C, Long G, Wolf J, Okerberg C, Herbert R (2002) Qualitative and quantitative analysis of nonneoplastic lesions in toxicology studies. Toxicol Pathol 30:93–96

    Article  Google Scholar 

  • Sotiropoulou PA, Perez SA, Gritzapis AD, Baxevanis CN, Papamichail M (2006) Interactions between human mesenchymal stem cells and natural killer cells. Stem Cells 24:74–85

    Article  Google Scholar 

  • Taki ZGE, Thilly W, Yaseen B, Lopez H, Mirza M, Hassuji Z, Vigneswaran S, Ahmed Abdi B, Hart A, Arumalla N, Thomas G, Denton CP, Suleman Y, Liu H, Venturini C, O’Reilly S, Xu S, Stratton R (2020) Pathogenic activation of mesenchymal stem cells is induced by the disease microenvironment in systemic sclerosis. Arthritis Rheumatol 72:1361–1374

    Article  CAS  Google Scholar 

  • Truchetet ME, Brembilla NC, Montanari E, Allanore Y, Chizzolini C (2011) Increased frequency of circulating Th22 in addition to Th17 and Th2 lymphocytes in systemic sclerosis: association with interstitial lung disease. Arthritis Res Therapy 13(5)

  • Valenzi E, Bulik M, Tabib T, Morse C, Sembrat J, Trejo Bittar H, Rojas M, Lafyatis R (2019) Single-cell analysis reveals fibroblast heterogeneity and myofibroblasts in systemic sclerosis-associated interstitial lung disease. Ann Rheum Dis 78:1379–1387

    Article  CAS  Google Scholar 

  • Wang CN, Lin YC, Chang BC, Chen CH, Wu R, Lee CC (2019) Targeting the phosphorylation site of myristoylated alanine-rich C kinase substrate alleviates symptoms in a murine model of steroid-resistant asthma. Brit J Pharmacol 176:1122–1134

    Article  CAS  Google Scholar 

  • Wang JL, Ren HZ, Yuan XW, Ma HC, Shi XL, Ding YT (2018) Interleukin-10 secreted by mesenchymal stem cells attenuates acute liver failure through inhibiting pyroptosis. Hepatol Res 48:E194–E202

    Article  CAS  Google Scholar 

  • Wolf D, Wolf AM (2008) Mesenchymal stem cells as cellular immunosuppressants. Lancet 371:1553–1554

    Article  Google Scholar 

  • Wynn TA (2008) Cellular and molecular mechanisms of fibrosis. J Pathol 214:199–210

    Article  CAS  Google Scholar 

  • Yew TL, Chang MC, Hsu YT, He FY, Weng WH, Tsai CC, Chiu FY, Hung SC (2013) Efficient expansion of mesenchymal stem cells from mouse bone marrow under hypoxic conditions. J Tissue Eng Regen M 7:984–993

    Article  CAS  Google Scholar 

  • Yim J, Koh J, Kim S, Song SG, Ahn HK, Kim YA, Jeon YK, Chung DH (2020) Effects of B7–H3 expression on tumour-infiltrating immune cells and clinicopathological characteristics in non-small-cell lung cancer. Eur J Cancer 133:74–85

    Article  CAS  Google Scholar 

  • Yoshizaki A, Yanaba K, Ogawa A, Asano Y, Kadono T, Sato S (2011) Immunization with DNA topoisomerase I and Freund’s complete adjuvant induces skin and lung fibrosis and autoimmunity via interleukin-6 signaling. Arthritis Rheum-Us 63:3575–3585

    Article  CAS  Google Scholar 

  • Zhao F, Zhang YF, Liu YG, Zhou JJ, Li ZK, Wu CG, Qi HW (2008) Therapeutic effects of bone marrow-derived mesenchymal stem cells engraftment on bleomycin-induced lung injury in rats. Transpl P 40:1700–1705

Download references

Funding

This work was supported by China Medical University (CMU108-S-28, CMU108-MF-78, CMU109-MF-84, and CMU110-MF-12). Financial support was provided by the Drug Development Center, China Medical University, from the Featured Areas Research Center Program within the framework of the Higher Education Sprout Project by the Ministry of Education (MOE) in Taiwan. Experiments and data analysis were performed in part using the Medical Research Core Facilities, Office of Research and Development at China Medical University, Taichung, Taiwan.

Author information

Authors and Affiliations

  1. Department of Microbiology and Immunology, School of Medicine, College of Medicine, China Medical University, No. 91 Hsueh‐Shih Road, Taichung, Taiwan

    Nithya Ganesan, Yu-Di Chang, Shih Tsung Fu & Chen-Chen Lee

  2. New Drug Development Center, China Medical University, Taichung, Taiwan

    Shih-Chieh Hung & Chen-Chen Lee

  3. Institute of Translation Medicine and New Drug Development, China Medical University, Taichung, Taiwan

    Shih-Chieh Hung

  4. Division of Immunology and Rheumatology, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan

    Joung-Liang Lan

  5. Graduate Institute of Veterinary Pathobiology, National Chung Hsing University, Taichung, Taiwan

    Jiunn-Wang Liao

Authors
  1. Nithya Ganesan
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yu-Di Chang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Shih-Chieh Hung
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Joung-Liang Lan
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jiunn-Wang Liao
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Shih Tsung Fu
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Chen-Chen Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

This study was designed, directed, and coordinated by C.-C.L. In addition, C.-C.L. provided conceptual and manuscript editing, performed the experiments, modulated the animal models, analyzed the data, and wrote and edited the manuscript. N.G, Y-D.C, S-C.H, J-L L, J-W L, and S-T. F conducted experiments and the data analysis.

Corresponding author

Correspondence to Chen-Chen Lee.

Ethics declarations

Ethics approval

The Animal Care and Use Committee of the China Medical University approved protocols for animal experiments (Protocol No. 2020–264).

Informed consent

Not applicable.

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

Below is the link to the electronic supplementary material.

Supplementary file1 (DOCX 2080 KB)

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ganesan, N., Chang, YD., Hung, SC. et al. Mesenchymal stem cells suppressed skin and lung inflammation and fibrosis in topoisomerase I-induced systemic sclerosis associated with lung disease mouse model. Cell Tissue Res 391, 323–337 (2023). https://doi.org/10.1007/s00441-022-03716-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00441-022-03716-8

Keywords

Search

Navigation