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Adenosine metabolism by mesenchymal stromal cells isolated from different human tissues

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Abstract

Mesenchymal stromal cells (MSCs) have unique biological properties and play important functions, which make them attractive tools for cell-based therapies. The basic mechanisms of these cells are not fully understood. However, the adenosinergic pathway contributes to the main effects attributed to MSCs. Adenosine is a highly immunosuppressive molecule and exerts a central role in inflammation by neutralizing the proinflammatory ATP influence. This nucleoside is produced by purinergic signaling, an important physiological pathway for MSCs, which involves proliferation, migration, differentiation, and apoptosis. Therefore, in this study, we analyzed the extracellular AMP hydrolysis and consequent adenosine production, as well as the expression of CD73 and adenosine receptors on the cell surface of MSCs isolated from different human tissues: dermis (D-MSCs), adipose tissue (AD-MSCs), and umbilical cord (UC-MSCs). All cells confirmed their multipotent capacity by adipogenic, osteogenic, and chondrogenic differentiation, as well as the expression of cell surface markers including CD44 + , CD105 + , and CD90 + . All MSCs expressed similar levels of CD73 and CD26 without a statistical difference among the different tissues, whereas ADA expression was lower in AD-MSCs. In addition, A1R and A3R mRNA levels were higher in D-MSCs and AD-MSCs, respectively. Enzymatic assay showed that AD-MSCs have the highest hydrolysis rate of AMP, leading to increased amount of adenosine production. Moreover, despite all MSCs completely hydrolyze extracellular AMP generating adenosine, the pattern of nucleosides metabolism was different. Therefore, although MSCs share certain characteristics as the multilineage potential and immunophenotype, they show different adenosinergic profiles according to tissue origin.

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References

  1. Friedenstein AJ, Piatetzky-Shapiro II, Petrakova KV. Osteogenesis in transplants of bone marrow cells. J Embryol Exp Morphol. 1966;16:381–90.

    CAS  PubMed  Google Scholar 

  2. Shammaa R, El-Kadiry AE-H, Abusarah J, Rafei M. Mesenchymal stem cells beyond regenerative medicine. Front Cell Dev Biol. 2020;8:72.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Fan X-L, Zhang Y, Li X, Fu Q-L. Mechanisms underlying the protective effects of mesenchymal stem cell-based therapy. Cell Mol Life Sci. 2020;77:2771–94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Galipeau J, Sensébé L. Mesenchymal stromal cells: clinical challenges and therapeutic opportunities. Cell Stem Cell. 2018;22:824–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Gao F, et al. Mesenchymal stem cells and immunomodulation: current status and future prospects. Cell Death Dis. 2016;7: e2062.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Dominici M, et al. Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy. 2006;8:315–7.

    Article  CAS  PubMed  Google Scholar 

  7. Galgaro BC, et al. The adenosinergic pathway in mesenchymal stem cell fate and functions. Med Res Rev. 2021. https://doi.org/10.1002/med.21796.

    Article  PubMed  Google Scholar 

  8. Roszek K, Wujak M. How to influence the mesenchymal stem cells fate? Emerging role of ectoenzymes metabolizing nucleotides. J Cell Physiol. 2018;234:320–34.

    Article  PubMed  Google Scholar 

  9. Burnstock G, Verkhratsky A. Long-term (trophic) purinergic signalling: purinoceptors control cell proliferation, differentiation and death. Cell Death Dis. 2010;1: e9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Chen X, et al. CD73 pathway contributes to the immunosuppressive ability of mesenchymal stem cells in intraocular autoimmune responses. Stem Cells Dev. 2016;25:337–46.

    Article  PubMed  Google Scholar 

  11. Saldanha-Araujo F, et al. Mesenchymal stromal cells up-regulate CD39 and increase adenosine production to suppress activated T-lymphocytes. Stem Cell Res. 2011;7:66–74. https://doi.org/10.1016/j.scr.2011.04.001.

    Article  CAS  PubMed  Google Scholar 

  12. Sattler C, et al. Inhibition of T-cell proliferation by murine multipotent mesenchymal stromal cells is mediated by CD39 expression and adenosine generation. Cell Transplant. 2011;20:1221–30.

    Article  PubMed  Google Scholar 

  13. de Lourdes Mora-García M, et al. Mesenchymal stromal cells derived from cervical cancer produce high amounts of adenosine to suppress cytotoxic T lymphocyte functions. J Transl Med. 2016;14:302.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Kerkelä E, et al. Adenosinergic immunosuppression by human mesenchymal stromal cells requires co-operation with T cells. Stem Cells. 2016;34:781–90.

    Article  PubMed  Google Scholar 

  15. Huang F, et al. Human gingiva-derived mesenchymal stem cells inhibit Xeno-graft-versus-host disease CD39-CD73-adenosine and IDO SIGNALS. Front Immunol. 2017;8:68.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Yan F, et al. Human dental pulp stem cells regulate allogeneic NK cells’ function via induction of anti-inflammatory purinergic signalling in activated NK cells. Cell Prolif. 2019;52: e12595.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Ferretti E, Horenstein AL, Canzonetta C, Costa F, Morandi F. Canonical and non-canonical adenosinergic pathways. Immunol Lett. 2019;205:25–30.

    Article  CAS  PubMed  Google Scholar 

  18. Merighi S, Gessi S, Borea PA. Adenosine receptors: structure, distribution, and signal transduction. In: Borea P, Varani K, Gessi S, Merighi S, Vincenzi F, editors. The adenosine receptors. Springer International Publishing; 2018. p. 33–57.

    Google Scholar 

  19. Beckenkamp LR, et al. Comparative characterization of CD271 and CD271− subpopulations of CD34 human adipose-derived stromal cells. J Cell Biochem. 2018;119:3873–84. https://doi.org/10.1002/jcb.26496.

    Article  CAS  PubMed  Google Scholar 

  20. Naasani LIS, et al. Comparison of human denuded amniotic membrane and porcine small intestine submucosa as scaffolds for limbal mesenchymal stem cells. Stem Cell Rev Rep. 2018;14:744–54. https://doi.org/10.1007/s12015-018-9819-8.

    Article  CAS  Google Scholar 

  21. Iser IC, et al. Conditioned medium from adipose-derived stem cells (ADSCs) promotes epithelial-to-mesenchymal-like transition (EMT-Like) in glioma cells in vitro. Mol Neurobiol. 2016;53:7184–99.

    Article  CAS  PubMed  Google Scholar 

  22. Glaser T, et al. Perspectives of purinergic signaling in stem cell differentiation and tissue regeneration. Purinergic Signal. 2012;8:523–37.

    Article  CAS  PubMed  Google Scholar 

  23. Naasani LIS, et al. Extracellular nucleotide hydrolysis in dermal and limbal mesenchymal stem cells: a source of adenosine production. J Cell Biochem. 2017;118:2430–42.

    Article  CAS  PubMed  Google Scholar 

  24. Naasani LIS, et al. Bioscaffold developed with decellularized human amniotic membrane seeded with mesenchymal stromal cells: assessment of efficacy and safety profiles in a second-degree burn preclinical model. Biofabrication. 2022;15(1):015012.

    Article  Google Scholar 

  25. Roszek K, Bomastek K, Drożdżal M, Komoszyński M. Dramatic differences in activity of purines metabolizing ecto-enzymes between mesenchymal stem cells isolated from human umbilical cord blood and umbilical cord tissue. Biochem Cell Biol. 2013;91:519–25.

    Article  CAS  PubMed  Google Scholar 

  26. Roszek K, et al. Canine adipose-derived stem cells: purinergic characterization and neurogenic potential for therapeutic applications. J Cell Biochem. 2017;118:58–65.

    Article  CAS  PubMed  Google Scholar 

  27. Tan K, et al. CD73 expression on mesenchymal stem cells dictates the reparative properties via its anti-inflammatory activity. Stem Cells Int. 2019;2019:8717694.

    Article  PubMed  PubMed Central  Google Scholar 

  28. Rodrigues C, et al. Bioglass 45S5: structural characterization of short range order and analysis of biocompatibility with adipose-derived mesenchymal stromal cells in vitro and in vivo. Mater Sci Eng C Mater Biol Appl. 2019;103:109781.

    Article  CAS  PubMed  Google Scholar 

  29. Beckenkamp LR, et al. Immortalization of mesenchymal stromal cells by TERT affects adenosine metabolism and impairs their immunosuppressive capacity. Stem Cell Rev Rep. 2020;16:776–91.

    Article  CAS  PubMed  Google Scholar 

  30. Iser IC, et al. Rat adipose-derived stromal cells (ADSCs) increases the glioblastoma growth and decreases the animal survival. Stem Cell Rev Rep. 2022;18:1495–509.

    Article  CAS  PubMed  Google Scholar 

  31. Mun CH, Kang M-I, Shin YD, Kim Y, Park Y-B. The Expression of immunomodulation-related cytokines and genes of adipose- and bone marrow-derived human mesenchymal stromal cells from early to late passages. Tissue Eng Regen Med. 2018;15:771–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Yang Y-HK, Ogando CR, Wang See C, Chang T-Y, Barabino GA. Changes in phenotype and differentiation potential of human mesenchymal stem cells aging in vitro. Stem Cell Res Ther. 2018;9:131.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Yourek G, Xin X, Reilly GC, Mao JJ. Infiltration of mesenchymal stem cells into PEGDA hydrogel. Biomed Mater Eng. 2014;24:1803–15.

    CAS  PubMed  Google Scholar 

  34. Wink MR, et al. Altered extracellular ATP, ADP and AMP catabolism in glioma cell lines. Cancer Lett. 2003;198:211–8.

    Article  CAS  PubMed  Google Scholar 

  35. Chen L, Wang Y, Fu X, Chen L. Novel optical nanoprobes for chemical and biological analysis. Springer; 2014.

    Book  Google Scholar 

  36. Wink MR, et al. Extracellular adenine nucleotides metabolism in astrocyte cultures from different brain regions. Neurochem Int. 2003;43:621–8. https://doi.org/10.1016/s0197-0186(03)00094-9.

    Article  CAS  PubMed  Google Scholar 

  37. Santin AP, Souza AFD, Brum LS, Furlanetto TW. Validation of reference genes for normalizing gene expression in real-time quantitative reverse transcription PCR in human thyroid cells in primary culture treated with progesterone and estradiol. Mol Biotechnol. 2013;54:278–82.

    Article  CAS  PubMed  Google Scholar 

  38. Kabat M, Bobkov I, Kumar S, Grumet M. Trends in mesenchymal stem cell clinical trials 2004–2018: is efficacy optimal in a narrow dose range? Stem Cells Transl Med. 2020;9:17–27.

    Article  CAS  PubMed  Google Scholar 

  39. Bernardo ME, Locatelli F, Fibbe WE. Mesenchymal stromal cells. Ann NY Acad Sci. 2009;1176:101–17. https://doi.org/10.1111/j.1749-6632.2009.04607.x.

    Article  CAS  PubMed  Google Scholar 

  40. Hass R, Kasper C, Böhm S, Jacobs R. Different populations and sources of human mesenchymal stem cells (MSC): a comparison of adult and neonatal tissue-derived MSC. Cell Commun Signal. 2011;9:12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Wegmeyer H, et al. Mesenchymal stromal cell characteristics vary depending on their origin. Stem Cells Dev. 2013;22:2606–18.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Hendijani F. Explant culture: An advantageous method for isolation of mesenchymal stem cells from human tissues. Cell Prolif. 2017;50:e12334.

    Article  PubMed  PubMed Central  Google Scholar 

  43. Skiles ML, Marzan AJ, Brown KS, Shamonki JM. Comparison of umbilical cord tissue-derived mesenchymal stromal cells isolated from cryopreserved material and extracted by explantation and digestion methods utilizing a split manufacturing model. Cytotherapy. 2020;22:581–91.

    Article  CAS  PubMed  Google Scholar 

  44. Mohamed-Ahmed S, et al. Adipose-derived and bone marrow mesenchymal stem cells: a donor-matched comparison. Stem Cell Res Ther. 2018;9:168.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Wu M, et al. Comparison of the biological characteristics of mesenchymal stem cells derived from the human placenta and umbilical cord. Sci Rep. 2018;8:5014.

    Article  PubMed  PubMed Central  Google Scholar 

  46. Majore I, Moretti P, Hass R, Kasper C. Identification of subpopulations in mesenchymal stem cell-like cultures from human umbilical cord. Cell Commun Signal. 2009;7:6.

    Article  PubMed  PubMed Central  Google Scholar 

  47. Zhang C, et al. Single-cell transcriptomic analysis reveals the cellular heterogeneity of mesenchymal stem cells. Genom Proteom Bioinform. 2022;20:70–86.

    Article  CAS  Google Scholar 

  48. Netsch P, et al. Human mesenchymal stromal cells inhibit platelet activation and aggregation involving CD73-converted adenosine. Stem Cell Res Ther. 2018;9:184.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Moreno E, et al. Molecular evidence of adenosine deaminase linking adenosine a receptor and CD26 proteins. Front Pharmacol. 2018;9:106.

    Article  PubMed  PubMed Central  Google Scholar 

  50. Roszek K, Porowińska D, Bajek A, Hołysz M, Czarnecka J. Chondrogenic differentiation of human mesenchymal stem cells results in substantial changes of ecto-nucleotides metabolism. J Cell Biochem. 2015;116:2915–23.

    Article  CAS  PubMed  Google Scholar 

  51. Young A, et al. A2AR adenosine signaling suppresses natural killer cell maturation in the tumor microenvironment. Cancer Res. 2018;78:1003–16.

    Article  CAS  PubMed  Google Scholar 

  52. Chatterjee D, et al. Natural killer cells acquire CD73 expression upon exposure to mesenchymal stem cells. Blood. 2014;123:594–5.

    Article  CAS  PubMed  Google Scholar 

  53. de Oliveira Bravo M, Carvalho JL, Saldanha-Araujo F. Adenosine production: a common path for mesenchymal stem-cell and regulatory T-cell-mediated immunosuppression. Purinergic Signal. 2016;12:595–609.

    Article  PubMed  PubMed Central  Google Scholar 

  54. Chen M, et al. Adoptive transfer of human gingiva-derived mesenchymal stem cells ameliorates collagen-induced arthritis via suppression of Th1 and Th17 cells and enhancement of regulatory T cell differentiation. Arthritis Rheum. 2013;65:1181–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Ni X, et al. Reduction in murine acute GVHD severity by human gingival tissue-derived mesenchymal stem cells via the CD39 pathways. Cell Death Dis. 2019;10:13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Abbas OL, et al. Comparative analysis of mesenchymal stem cells from bone marrow, adipose tissue, and dental pulp as sources of cell therapy for zone of stasis burns. J Invest Surg. 2019;32:477–90.

    Article  PubMed  Google Scholar 

  57. Naasani LIS, Sévigny J, Moulin VJ, Wink MR. UTP increases wound healing in the self assembled skin substitute (SASS). J Cell Commun Signal. 2023. https://doi.org/10.1007/s12079-023-00725-2.

    Article  PubMed  PubMed Central  Google Scholar 

  58. Yoo KH, et al. Comparison of immunomodulatory properties of mesenchymal stem cells derived from adult human tissues. Cell Immunol. 2009;259:150–6.

    Article  CAS  PubMed  Google Scholar 

  59. Valencia J, et al. Comparative analysis of the immunomodulatory capacities of human bone marrow- and adipose tissue-derived mesenchymal stromal cells from the same donor. Cytotherapy. 2016;18:1297–311.

    Article  CAS  PubMed  Google Scholar 

  60. Ribeiro A, et al. Mesenchymal stem cells from umbilical cord matrix, adipose tissue and bone marrow exhibit different capability to suppress peripheral blood B, natural killer and T cells. Stem Cell Res Ther. 2013;4:125.

    Article  PubMed  PubMed Central  Google Scholar 

  61. Melief SM, Zwaginga JJ, Fibbe WE, Roelofs H. Adipose tissue-derived multipotent stromal cells have a higher immunomodulatory capacity than their bone marrow-derived counterparts. Stem Cells Transl Med. 2013;2:455–63.

    Article  PubMed  PubMed Central  Google Scholar 

  62. Herman-de-Sousa C, et al. Opposing effects of adenosine and inosine in human subcutaneous fibroblasts may be regulated by third party ADA cell providers. Cells. 2020;9(3):651–672.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Haskó G, et al. Inosine inhibits inflammatory cytokine production by a posttranscriptional mechanism and protects against endotoxin-induced shock. J Immunol. 2000;164:1013–9.

    Article  PubMed  Google Scholar 

  64. Katebi M, Soleimani M, Cronstein BN. Adenosine A2Areceptors play an active role in mouse bone marrow-derived mesenchymal stem cell development. J Leukoc Biol. 2009;85:438–44. https://doi.org/10.1189/jlb.0908520.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Corciulo C, et al. Endogenous adenosine maintains cartilage homeostasis and exogenous adenosine inhibits osteoarthritis progression. Nat Commun. 2017;8:15019.

    Article  PubMed  PubMed Central  Google Scholar 

  66. Dang J, et al. Human gingiva-derived mesenchymal stem cells are therapeutic in lupus nephritis through targeting of CD39CD73 signaling pathway. J Autoimmun. 2020;113: 102491.

    Article  CAS  PubMed  Google Scholar 

  67. Li X, et al. Comprehensive characterization of four different populations of human mesenchymal stem cells as regards their immune properties, proliferation and differentiation. Int J Mol Med. 2014;34:695–704.

    Article  PubMed  PubMed Central  Google Scholar 

  68. Carroll SH, et al. A2B adenosine receptor promotes mesenchymal stem cell differentiation to osteoblasts and bone formation in vivo. J Biol Chem. 2012;287:15718–27.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. D’Alimonte I, et al. Osteogenic differentiation of mesenchymal stromal cells: a comparative analysis between human subcutaneous adipose tissue and dental pulp. Stem Cells Dev. 2017;26:843–55.

    Article  PubMed  Google Scholar 

  70. Zuccarini M, et al. Multipotent stromal cells from subcutaneous adipose tissue of normal weight and obese subjects: modulation of their adipogenic differentiation by adenosine a receptor ligands. Cells. 2021;10(12):3560–3581.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The authors are very thankful to the Plastic Surgery Service and the Obstetric Center from Santa Casa de Misericórdia de Porto Alegre (ISCMPA) for the discarded tissues’ donation for this study.

Funding

All students are recipients of fellowships from Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) and Marcia R. Wink is recipient of level 1 PQ research fellowship from Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq). This study was supported by CNPq MS-SCTIE-Decit/CNPq no 12/2018 (441575/2018–8); MS-SCTIE-DECIT-DGITIS-CGCIS/CNPq nº 26/2020 (442586/2020–5), and National Institute of Science and Technology in 3D printing and Advanced Materials Applied to Human and Veterinary Health—INCT _3D-Saúde, CNPq (406436/2022–3); Fundação de Amparo à Pesquisa do Estado do Rio Grande do Sul, EDITAL FAPERGS 07/2021—PROGRAMA PESQUISADOR GAÚCHO—PqG (21/2551–0001947-6) and RITES (22/2551–0000385-0);

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  1. Laboratório de Biologia Celular, Universidade Federal de Ciências da Saúde de Porto Alegre, UFCSPA, Rua Sarmento Leite, 245, Porto Alegre, RS, CEP 90050-170, Brazil

    Bruna Campos Galgaro, Liziane Raquel Beckenkamp, Liliana I. Sous Naasani & Márcia Rosângela Wink

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  1. Bruna Campos Galgaro
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  2. Liziane Raquel Beckenkamp
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  3. Liliana I. Sous Naasani
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  4. Márcia Rosângela Wink
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BCG, LRB, and LISN did the experiments; BCG wrote the paper; LRB, LISN, and MRW reviewed the paper; MRW obtained the grants and supervised the experiments.

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Correspondence to Márcia Rosângela Wink.

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Galgaro, B.C., Beckenkamp, L.R., Naasani, L.I.S. et al. Adenosine metabolism by mesenchymal stromal cells isolated from different human tissues. Human Cell 36, 2247–2258 (2023). https://doi.org/10.1007/s13577-023-00957-9

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