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Human umbilical cord-derived mesenchymal stem cells ameliorate psoriasis-like dermatitis by suppressing IL-17-producing γδ T cells

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Abstract

Mesenchymal stem cells (MSCs) have shown great potential in treating autoimmune diseases due to their immunomodulatory capability, which has been verified in both animal experiments and clinical trials. Psoriasis is a chronic and remitting immune-related disease. Limited studies have demonstrated that MSCs might be an effective therapeutic approach for managing psoriasis, whose underlying mechanism remains to be elucidated. In our present study, human umbilical cord-derived MSCs (hUC-MSCs) were subcutaneously injected into mice with imiquimod (IMQ)-induced psoriasis-like skin inflammation to explore the feasibility of this cellular therapy. The severity of psoriasis-like dermatitis was evaluated by cumulative psoriasis area and severity index score and epidermal thickness of skin tissue sections. Flow cytometric analysis was utilized to detect T helper cells, regulatory T cells, and γδ T cells in skin-draining lymph nodes. Real-time quantitative polymerase chain reaction and enzyme-linked immunosorbent assay were used to assess the expression levels of psoriasis-related cytokines and chemokines in mouse dorsal skin lesions. We discovered that hUC-MSCs drastically diminished the severity of IMQ-induced psoriasis-like dermatitis and suppressed inflammatory cell response. Although the tail vein injection of hUC-MSCs was also effective, it was correlated with higher mortality owing to pulmonary embolism. By comparison, subcutaneous injection with two million hUC-MSCs was identified to be the optimal therapeutic strategy. Furthermore, we uncovered that hUC-MSCs might repress skin inflammation probably through inhibiting interleukin-17-producing γδ T cells. In conclusion, subcutaneous administration of hUC-MSCs might be a promising therapeutic approach for psoriasis. Our findings provide novel insights into the underpinning mechanism of hUC-MSC treatment in the management of psoriasis.

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Availability of data and materials

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

Abbreviations

MSCs:

Mesenchymal stem cells

hUC-MSCs:

Human umbilical cord-derived MSCs

IMQ:

Imiquimod

RA:

Rheumatoid arthritis

SOP:

Standard operating procedure

IL:

Interleukin

BCA:

Bicinchoninic acid

TNF:

Tumor necrosis factor

IFN:

Interferon

LN:

Lymph nodes

BM:

Bone marrow

PASI:

Psoriasis area severity index

TGF:

Transforming growth factor

Th17:

T helper 17

PBS:

Phosphate-buffered saline

H&E:

Hematoxylin and eosin

SLE:

Systemic lupus erythematosus

ECM1:

Extracellular matrix protein 1

MCAM:

Melanoma cell adhesion molecule

References

  • Albanesi C, Madonna S, Gisondi P, Girolomoni G (2018) The interplay between keratinocytes and immune cells in the pathogenesis of psoriasis. Front Immunol 9:1549

    Article  Google Scholar 

  • Alves de Medeiros AK, Speeckaert R, Desmet E, Van Gele M, De Schepper S, Lambert J (2016) JAK3 as an emerging target for topical treatment of inflammatory skin diseases. PLoS One 11:e0164080

  • Arturo J, Perez C, Larios L, Segura O, Bastidas Y, Segura O, Lucena C, Lucena E, Ruiz C (2014) Immunomodulation and induction of remission in crohn's disease with autologous expanded mesenchymal stem cells. case report. Cytotherapy 16:S101

  • Bandyopadhyay M, Larregina AT (2020) Keratinocyte-polyamines and dendritic cells: a bad duet for psoriasis. Immunity 53:16–18

    Article  CAS  Google Scholar 

  • Bernardo ME, Fibbe WE (2013) Mesenchymal stromal cells: sensors and switchers of inflammation. Cell Stem Cell 13:392–402

    Article  CAS  Google Scholar 

  • Blauvelt A, Chiricozzi A (2018) The immunologic role of IL-17 in psoriasis and psoriatic arthritis pathogenesis. Clin Rev Allergy Immunol 55:379–390

    Article  CAS  Google Scholar 

  • Boehncke WH, Schön MP (2015) Psoriasis. Lancet (london, England) 386:983–994

    Article  CAS  Google Scholar 

  • Chen H, Niu JW, Ning HM, Pan X, Li XB, Li Y, Wang DH, Hu LD, Sheng HX, Xu M et al (2016) Treatment of psoriasis with mesenchymal stem cells. Am J Med 129:e13-14

    Article  Google Scholar 

  • Chen M, Peng J, Xie Q, Xiao N, Su X, Mei H, Lu Y, Zhou J, Dai Y, Wang S et al (2019a) Mesenchymal stem cells alleviate moderate-to-severe psoriasis by reducing the production of type i interferon (IFN-I) by plasmacytoid dendritic cells (pDCs). Stem Cells Int 2019:6961052

    PubMed  PubMed Central  Google Scholar 

  • Chen Y, Yu Q, Hu Y, Shi Y (2019b) Current research and use of mesenchymal stem cells in the therapy of autoimmune diseases. Curr Stem Cell Res Ther 14:579–582

    Article  CAS  Google Scholar 

  • Choi EW, Shin IS, Song JW, Lee M, Yun TW, Yang J, Choi KS, Kim SJ (2016) Effects of transplantation of CTLA4Ig-overexpressing adipose tissue-derived mesenchymal stem cells in mice with sustained severe rheumatoid arthritis. Cell Transplant 25:243–259

    Article  Google Scholar 

  • Conrad C, Gilliet M (2018) Psoriasis: from pathogenesis to targeted therapies. Clin Rev Allergy Immunol 54:102–113

    Article  CAS  Google Scholar 

  • De Jesus MM, Santiago JS, Trinidad CV, See ME, Semon KR, Fernandez MO Jr, Chung FS (2016) Autologous adipose-derived mesenchymal stromal cells for the treatment of psoriasis vulgaris and psoriatic arthritis: a case report. Cell Transplant 25:2063–2069

    Article  Google Scholar 

  • Dietz AB, Dozois EJ, Fletcher JG, Butler GW, Radel D, Lightner AL, Dave M, Friton J, Nair A, Camilleri ET et al (2017) Autologous mesenchymal stem cells, applied in a bioabsorbable matrix, for treatment of perianal fistulas in patients with Crohn’s disease. Gastroenterology 153:59-62.e52

    Article  CAS  Google Scholar 

  • Fitzgerald O, Winchester R (2014) Editorial: emerging evidence for critical involvement of the interleukin-17 pathway in both psoriasis and psoriatic arthritis. Arthritis & Rheumatology (hoboken, NJ) 66:1077–1080

    Article  CAS  Google Scholar 

  • Gallo R, Gambelli F, Gava B, Sasdelli F, Tellone V, Masini M, Marchetti P, Dotta F, Sorrentino V (2007) Generation and expansion of multipotent mesenchymal progenitor cells from cultured human pancreatic islets. Cell Death Differ 14:1860–1871

    Article  CAS  Google Scholar 

  • Gray EE, Suzuki K, Cyster JG (2011) Cutting edge: identification of a motile IL-17-producing gammadelta T cell population in the dermis. J Immunol 186:6091–6095

    Article  CAS  Google Scholar 

  • Han Y, Mora J, Huard A, da Silva P, Wiechmann S, Putyrski M, Schuster C, Elwakeel E, Lang G, Scholz A et al (2019) IL-38 Ameliorates skin inflammation and limits IL-17 production from γδ T cells. Cell Rep 27:835-846.e835

    Article  CAS  Google Scholar 

  • Hartwig T, Pantelyushin S, Croxford AL, Kulig P, Becher B (2015) Dermal IL-17-producing γδ T cells establish long-lived memory in the skin. Eur J Immunol 45:3022–3033

    Article  CAS  Google Scholar 

  • Hijnen D, Knol EF, Gent YY, Giovannone B, Beijn SJ, Kupper TS, Bruijnzeel-Koomen CA, Clark RA (2013) CD8(+) T cells in the lesional skin of atopic dermatitis and psoriasis patients are an important source of IFN-γ, IL-13, IL-17, and IL-22. J Invest Dermatol 133:973–979

    Article  CAS  Google Scholar 

  • Hou R, Liu R, Niu X, Chang W, Yan X, Wang C, Li J, An P, Li X, Yin G et al (2014a) Biological characteristics and gene expression pattern of bone marrow mesenchymal stem cells in patients with psoriasis. Exp Dermatol 23:521–523

    Article  CAS  Google Scholar 

  • Hou R, Yan H, Niu X, Chang W, An P, Wang C, Yang Y, Yan X, Li J, Liu R et al (2014b) Gene expression profile of dermal mesenchymal stem cells from patients with psoriasis. J Eur Acad Dermatol Venereol: JEADV 28:1782–1791

  • Hu Y, Chen Z, Gong Y, Shi Y (2018) A review of switching biologic agents in the treatment of moderate-to-severe plaque psoriasis. Clin Drug Investig 38:191–199

    Article  CAS  Google Scholar 

  • Jee MH, Mraz V, Geisler C, Bonefeld CM (2020) γδ T cells and inflammatory skin diseases. Immunol Rev

  • Kim N, Lee S, Kang J, Choi YA, Lee B, Kwon TK, Jang YH, Kim SH (2020) Hispidulin alleviates imiquimod-induced psoriasis-like skin inflammation by inhibiting splenic Th1/Th17 cell population and keratinocyte activation. Int Immunopharmacol 87:106767

  • Küçük C, Jiang B, Hu X, Zhang W, Chan JK, Xiao W, Lack N, Alkan C, Williams JC, Avery KN et al (2015) Activating mutations of STAT5B and STAT3 in lymphomas derived from γδ-T or NK cells. Nat Commun 6:6025

    Article  Google Scholar 

  • Mak RK, Hundhausen C, Nestle FO (2009) Progress in understanding the immunopathogenesis of psoriasis. Actas Dermosifiliogr 100(Suppl 2):2–13

    Article  Google Scholar 

  • Nestle FO, Kaplan DH, Barker J (2009) Psoriasis. N Engl J Med 361:496–509

    Article  CAS  Google Scholar 

  • Niu X, Chang W, Liu R, Hou R, Li J, Wang C, Li X, Zhang K (2016a) Expression of pro-angiogenic genes in mesenchymal stem cells derived from dermis of patients with psoriasis. Int J Dermatol 55:e280-288

    Article  CAS  Google Scholar 

  • Niu X, Chang W, Liu R, Hou R, Li J, Wang C, Li X, Zhang K (2016b) mRNA and protein expression of the angiogenesis-related genes EDIL3, AMOT and ECM1 in mesenchymal stem cells in psoriatic dermis. Clin Exp Dermatol 41:533–540

    Article  CAS  Google Scholar 

  • Paganelli A, Tarentini E, Benassi L, Kaleci S, Magnoni C (2020) Mesenchymal stem cells for the treatment of psoriasis: a comprehensive review. Clin Exp Dermatol

  • Prinz I, Sandrock I (2015) γδ T cells come to stay: innate skin memory in the aldara model. Eur J Immunol 45:2994–2997

    Article  CAS  Google Scholar 

  • Ryan JM, Barry FP, Murphy JM, Mahon BP (2005) Mesenchymal stem cells avoid allogeneic rejection. J Inflamm (London, England) 2:8

    Article  Google Scholar 

  • Sah SK, Park KH, Yun CO, Kang KS, Kim TY (2016) Effects of human mesenchymal stem cells transduced with superoxide dismutase on imiquimod-induced psoriasis-like skin inflammation in mice. Antioxid Redox Signal 24:233–248

  • Sato Y, Ogawa E, Okuyama R (2020) Role of innate immune cells in psoriasis. Int J Mol Sci 21

  • Shi Y, Wang Y, Li Q, Liu K, Hou J, Shao C, Wang Y (2018) Immunoregulatory mechanisms of mesenchymal stem and stromal cells in inflammatory diseases. Nat Rev Nephrol 14:493–507

    Article  CAS  Google Scholar 

  • Song N, Scholtemeijer M, Shah K (2020) Mesenchymal stem cell immunomodulation: mechanisms and therapeutic potential. Trends Pharmacol Sci

  • Subedi S, Gong Y, Chen Y, Shi Y (2019) Infliximab and biosimilar infliximab in psoriasis: efficacy, loss of efficacy, and adverse events. Drug Des Devel Ther 13:2491–2502

    Article  CAS  Google Scholar 

  • Sun L, Wang D, Liang J, Zhang H, Feng X, Wang H, Hua B, Liu B, Ye S, Hu X et al (2010) Umbilical cord mesenchymal stem cell transplantation in severe and refractory systemic lupus erythematosus. Arthritis Rheum 62:2467–2475

    Article  CAS  Google Scholar 

  • Toussirot E (2012) The IL23/Th17 pathway as a therapeutic target in chronic inflammatory diseases. Inflamm Allergy Drug Targets 11:159–168

    Article  CAS  Google Scholar 

  • van der Fits L, Mourits S, Voerman JS, Kant M, Boon L, Laman JD, Cornelissen F, Mus AM, Florencia E, Prens EP et al (2009) Imiquimod-induced psoriasis-like skin inflammation in mice is mediated via the IL-23/IL-17 axis. J Immunol 182:5836–5845

    Article  Google Scholar 

  • Vizoso FJ, Eiro N, Costa L, Esparza P, Landin M, Diaz-Rodriguez P, Schneider J, Perez-Fernandez R (2019) Mesenchymal stem cells in homeostasis and systemic diseases: hypothesis, evidences, and therapeutic opportunities. Int J Mol Sci 20

  • Wang H, Qiu X, Ni P, Qiu X, Lin X, Wu W, Xie L, Lin L, Min J, Lai X et al (2014) Immunological characteristics of human umbilical cord mesenchymal stem cells and the therapeutic effects of their transplantion on hyperglycemia in diabetic rats. Int J Mol Med 33:263–270

    Article  Google Scholar 

  • Wang L, Wang L, Cong X, Liu G, Zhou J, Bai B, Li Y, Bai W, Li M, Ji H et al (2013) Human umbilical cord mesenchymal stem cell therapy for patients with active rheumatoid arthritis: safety and efficacy. Stem Cells and Development 22:3192–3202

    Article  CAS  Google Scholar 

  • Wang SG, Hsu NC, Wang SM, Wang FN (2020) Successful treatment of plaque psoriasis with allogeneic gingival mesenchymal stem cells: a case study. Case Rep Dermatol Med 2020:4617520

    PubMed  PubMed Central  Google Scholar 

  • Wu JJ, Valdecantos WC (2017) Adalimumab in chronic plaque psoriasis: a clinical guide. J Drugs Dermatol 16:779–790

    CAS  PubMed  Google Scholar 

  • Xie XJ, Di TT, Wang Y, Wang MX, Meng YJ, Lin Y, Xu XL, Li P, Zhao JX (2018) Indirubin ameliorates imiquimod-induced psoriasis-like skin lesions in mice by inhibiting inflammatory responses mediated by IL-17A-producing γδ T cells. Mol Immunol 101:386–395

    Article  CAS  Google Scholar 

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Acknowledgements

Not applicable.

Funding

This work was sponsored by grants from National Natural Science Foundation of China (No. 81872522, 82073429, 81903205, 81803120, and 81900612), the National Key Research and Development Program of China (No. 2018YFC1705301, 2018YFC1705305), Innovation Program of Shanghai Municipal Education Commission (No. 2019–01-07–00-07-E00046), the Program of Science and Technology Commission of Shanghai Municipality (No. 18140901800), Excellent Subject Leader Program of Shanghai Municipal Commission of Health and Family Planning (No. 2018BR30), Clinical Research Program of Shanghai Hospital Development Center (No. SHDC2020CR1014B, SHDC12018X06), Shanghai Sailing Program (No. 19YF1438100), Program of Shanghai Academic Research Leader (No. 20XD1403300), the Fundamental Research Funds for the Central Universities (#22120210566), and Research Program of Shanghai Skin Disease Hospital (No. 2019KYQD08).

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Author notes

  1. Youdong Chen, Yifan Hu and Xue Zhou are contributed to this article equally.

Authors and Affiliations

  1. Department of Dermatology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai, 200072, China

    Youdong Chen, Yifan Hu, Xue Zhou, Qian Yu, Zeyu Chen, Peng Xu, Zengyang Yu & Yuling Shi

  2. Department of Dermatology, Shanghai Skin Disease Hospital, Tongji University School of Medicine, Shanghai, 200443, China

    Youdong Chen, Yifan Hu, Xue Zhou, Zihan Zhao, Yuanyuan Wang, Chunyuan Guo, Xilin Zhang & Yuling Shi

  3. Institute of Psoriasis, Tongji University School of Medicine, Shanghai, 200443, China

    Youdong Chen, Yifan Hu, Xue Zhou, Zihan Zhao, Qian Yu, Zeyu Chen, Yuanyuan Wang, Peng Xu, Zengyang Yu, Chunyuan Guo, Xilin Zhang & Yuling Shi

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Contributions

Youdong Chen contributed to conception and design, provision of study material, collection and assembly of data, data analysis and interpretation, manuscript writing, and final approval of manuscript. Yifan Hu was involved in conception and design, provision of study material, collection and assembly of data, data analysis and interpretation, and manuscript writing. Xue Zhou contributed to conception and design, provision of study material, collection and assembly of data, and data analysis and interpretation. Zihan Zhao, Peng Xu, Qian Yu, Zengyang Yu, Zeyu Chen, and Yuanyuan Wang contributed to provision of study material and data analysis and interpretation. Chunyuan Guo was involved in conception and design, financial support, provision of study material, data analysis and interpretation, and final approval of manuscript. Xilin Zhang contributed to provision of study material, collection and assembly of data, data analysis and interpretation, manuscript writing, and final approval of manuscript. Yuling Shi contributed to conception and design, financial support, administrative support, provision of study material, collection and assembly of data, data analysis and interpretation, manuscript writing, and final approval of manuscript.

Corresponding authors

Correspondence to Chunyuan Guo, Xilin Zhang or Yuling Shi.

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All mouse studies were approved by the Institutional Animal Experiment Committee of the Tongji University School of Medicine and were performed in accordance with institutional and governmental guidelines.

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441_2022_3616_MOESM1_ESM.tif

Supplementary file1 Fig. S1 Schematic of the experimental procedures. a Experimental design of Fig. 2. b Experimental design of Fig. 3. c Experimental design of Fig. 4. d Experimental design of Fig. 5 (TIF 284 KB)

441_2022_3616_MOESM2_ESM.tif

Supplementary file2 Fig. S2 The number of injection points, time points of administration, or injection volumes do not influence the therapeutic effects of hUC-MSCs. a Disease model mice were subcutaneously injected with two million hUC-MSCs on day 0 at one injection point in 500 μl PBS (group A), at five injection points in 500 μl PBS (group B), at one injection point in 200 μl PBS (group C); group D was only given 200 μl PBS at one injection point. The experimental mice were sacrificed after six consecutive days of IMQ application (n = 54, three independent experiments, three mice for each group, and 18 mice for each experiment). b Representative pictures of mouse skin lesions. c Evaluation of PASI score. d H&E staining and calculated epidermal thicknesses e. * indicates comparison with untreated psoriatic group and unpaired t test was used for statistical analysis. *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001 (TIF 986 KB)

441_2022_3616_MOESM3_ESM.tif

Supplementary file3 Fig. S3 hUC-MSC treatment modulates the expression of inflammatory cytokines and chemokines. Mice were treated as in Fig. 5. Dorsal skin samples from control mice, disease model mice, and hUC-MSC-treated IMQ mice were collected, and IL-4, IL-10, IL-6, IL-17, IL-22, IL-23A, IL-1β, TNF-α, IFN-γ, TGF-β, and CXCL-15 mRNA expression was analyzed by quantitative RT-qPCR (n = 48, four independent experiments, three mice for each group and 12 mice for each experiment). The data are the mean ± SEM, and unpaired t test was used for statistical analysis. * indicates comparison with untreated psoriatic group and unpaired t test was used for statistical analysis. *P < 0.05. (TIF 441 KB)

441_2022_3616_MOESM4_ESM.tif

Supplementary file4 Fig. S4 hUC-MSCs do not alter IL-6 and TNF-α protein production. Mice were treated as in Fig. 5. Dorsal skin samples from control mice, disease model mice, and hUC-MSC-treated IMQ mice were collected, and protein levels of IL-6 a and TNF-α b were evaluated quantitatively by ELISA (n = 48, four independent experiments, three mice for each group, and 12 mice for each experiment). The data are the mean ± SEM, and unpaired t test was used for statistical analysis. * indicates comparison with untreated psoriatic group and unpaired t test was used for statistical analysis. *P < 0.05. (TIF 84 KB)

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Chen, Y., Hu, Y., Zhou, X. et al. Human umbilical cord-derived mesenchymal stem cells ameliorate psoriasis-like dermatitis by suppressing IL-17-producing γδ T cells. Cell Tissue Res 388, 549–563 (2022). https://doi.org/10.1007/s00441-022-03616-x

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