CoChat
Sign Up
Cited by 55Extracellular vesicles in diseaseWound Healing and TreatmentsMesenchymal stem cell research

The DOI matches its Crossref record; 4 of the 4 references it cites were found in a registry or an index.

3D-MSCs A151 ODN-loaded exosomes are immunomodulatory and reveal a proteomic cargo that sustains wound resolution

Open access
Camões, Sérgio P., Bulut, Ozlem, Yazar, Volkan, Gaspar, Maria M., Simões, Sandra, Ferreira, Rita, Vitorino, Rui, Santos, Jorge M., Gursel, Ihsan, Miranda, Joana P.·2022·Journal of Advanced Research
DOI 10.1016/j.jare.2022.01.013PMC PMC9637564
Open this paper in CoChat — free accountOpen PDF

Abstract

INTRODUCTION: Non-healing wounds remain a major burden due to the lack of effective treatments. Mesenchymal stem cell-derived exosomes (MSC-Exo) have emerged as therapeutic options given their pro-regenerative and immunomodulatory features. Still, little is known on the exact mechanisms mediated by MSC-Exo. Importantly, modulation of their efficacy through 3D-physiologic cultures together with loading strategies continues underexplored. OBJECTIVES: To uncover the MSC-Exo-mediated mechanism via proteomic analyses, and to use 3D-culture and loading technologies to expand MSC-Exo efficacy for cutaneous wound healing. METHODS: MSC-Exo were produced in either 3D or 2D cultures (Exo3D/Exo2D) and loaded with an exogenous immunosuppressive oligodeoxynucleotide (A151 ODN). Both, loaded and naïve exosomes were characterised regarding size, morphology and the presence of specific protein markers; while IPA analyses enabled to correlate their protein content with the effects observed in vitro and in vivo. The Exo3D/Exo2D regenerative potential was evaluated in vitro by assessing keratinocyte and fibroblast mitogenicity, motogenicity, and cytokine secretion as well as using an in vivo wound splinting model. Accordingly, the modulation of inflammatory and immune responses by A151-loaded Exo3D/Exo2D was also assessed. RESULTS: Exo3D stimulated mitogenically and motogenically keratinocytes and fibroblasts in vitro, with upregulation of IL-1α and VEGF-α or increased secretion of TGF-β, TNF-α and IL-10. In vivo, Exo3D reduced the granulation tissue area and promoted complete re-epithelization of the wound. These observations were sustained by the proteomic profiling of the Exo3D cargo that identified wound healing-related proteins, such as TGF-β, ITGA1-3/5, IL-6, CDC151, S100A10 and Wnt5α. Moreover, when loaded with A151 ODN, Exo3D differentially mediated wound healing-related trophic factors reducing the systemic levels of IL-6 and TNF-α at the late stage of wound healing in vivo. CONCLUSION: Our results support the potential of A151-loaded Exo3D for the treatment of chronic wounds by promoting skin regeneration, while modulating the systemic levels of the pro-inflammatory cytokines.

Overview

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1016/j.jare.2022.01.013

Cites

4 of 4 references verified0 citation errors · 0 not checkable

Statistics

Verification

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • MSCs empower resident cells through the secretion of trophic factors, inducing those cells to regenerate damaged tissue.

    “MSCs were shown to empower the resident cells through the secretion of trophic factors, inducing those cells to regenerate the damaged tissue [7], [8], [9], [10].”

    From Mesenchymal stem cell secretome for regenerative medicine: Where do we stand? (2025) · cites this paper as [9]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Citations

Cites

Flagged first, then by citations

Research works printed but not linked: 67

  1. Martin, 1997, Wound Healing-Aiming for Perfect Skin Regeneration, Science, 276, 75, 10.1126/science.276.5309.75 · DOI
  2. Lindholm, 2016, Wound management for the 21st century: combining effectiveness and efficiency, Int Wound J, 13, 5, 10.1111/iwj.12623 · DOI
  3. Duscher, 2016, Stem Cells in Wound Healing: The Future of Regenerative Medicine?, A Mini-Review. Gerontology, 62, 216
  4. Frykberg, 2015, Challenges in the Treatment of Chronic Wounds, Adv Wound Care, 4, 560, 10.1089/wound.2015.0635 · DOI
  5. Han, 2017, Chronic Wound Healing: A Review of Current Management and Treatments, Adv Ther, 34, 599, 10.1007/s12325-017-0478-y · DOI
  6. Jones, 2006, Wound dressings, BMJ, 332, 777, 10.1136/bmj.332.7544.777 · DOI
  7. Sun, 2014, Advances in skin grafting and treatment of cutaneous wounds, Science (80-), 346, 941, 10.1126/science.1253836 · DOI · Paper page
  8. Smiell, 1999, Efficacy and safety of becaplermin (recombinant human platelet-derived growth factor-BB) in patients with nonhealing, lower extremity diabetic ulcers: a combined analysis of four randomized studies, Wound Repair Regen, 7, 335, 10.1046/j.1524-475X.1999.00335.x · DOI · Paper page
  9. Liu, 2006, Wound Repair by Bone Marrow Stromal Cells through Growth Factor Production, J Surg Res, 136, 336, 10.1016/j.jss.2006.07.037 · DOI
  10. Miranda, 2019, The Secretome Derived From 3D-Cultured Umbilical Cord Tissue MSCs Counteracts Manifestations Typifying Rheumatoid Arthritis, Front Immunol, 10, 10.3389/fimmu.2019.00018 · DOI · Paper page
  11. Bárcia, 2015, What Makes Umbilical Cord Tissue-Derived Mesenchymal Stromal Cells Superior Immunomodulators When Compared to Bone Marrow Derived Mesenchymal Stromal Cells?, Stem Cells Int, 2015, 1, 10.1155/2015/583984 · DOI
  12. Becker, 2016, Homing and migration of mesenchymal stromal cells: How to improve the efficacy of cell therapy?, World J Stem Cells, 8, 73, 10.4252/wjsc.v8.i3.73 · DOI
  13. Legaki, 2016, Therapeutic Potential of Secreted Molecules Derived from Human Amniotic Fluid Mesenchymal Stem/Stroma Cells in a Mice Model of Colitis, Stem Cell Rev Reports, 12, 604, 10.1007/s12015-016-9677-1 · DOI
  14. Zagoura, 2012, Therapeutic potential of a distinct population of human amniotic fluid mesenchymal stem cells and their secreted molecules in mice with acute hepatic failure, Gut, 61, 894, 10.1136/gutjnl-2011-300908 · DOI
  15. Teixeira FG, Carvalho MM, Panchalingam KM, Rodrigues AJ, Mendes-Pinheiro B, Anjo S, et al. Impact of the Secretome of Human Mesenchymal Stem Cells on Brain Structure and Animal Behavior in a Rat Model of Parkinson’s Disease. Stem Cells Transl Med 2017;6:634–46. https://doi.org/10.5966/sctm.2016-0071. · DOI
  16. Hassan Famian M, Montazer Saheb S, Montaseri A. Conditioned Medium of Wharton’s Jelly Derived Stem Cells Can Enhance the Cartilage Specific Genes Expression by Chondrocytes in Monolayer and Mass Culture Systems. Adv Pharm Bull 2017;7:123–30. https://doi.org/10.15171/apb.2017.016. · DOI
  17. Sevivas, 2017, Mesenchymal Stem Cell Secretome: A Potential Tool for the Prevention of Muscle Degenerative Changes Associated With Chronic Rotator Cuff Tears, Am J Sports Med, 45, 179, 10.1177/0363546516657827 · DOI
  18. Camões SP, Santos JM, Carvalho F, Miranda JP. Mesenchymal Stem Cells for Cutaneous Wound Healing. In: Rodrigues G, Roelen BAJ, editors. Concepts Appl. Stem Cell Biol., 2020, p. 247–67. https://doi.org/10.1007/978-3-030-43939-2_13. · DOI · Paper page
  19. Jahoda, 2001, Hair follicle dermal sheath cells: unsung participants in wound healing, Lancet, 358, 1445, 10.1016/S0140-6736(01)06532-1 · DOI
  20. Hu, 2018, Mesenchymal Stromal Cells and Cutaneous Wound Healing: A Comprehensive Review of the Background, Role, and Therapeutic Potential, Stem Cells Int, 2018, 1, 10.1155/2018/7412304 · DOI
  21. Casado-Díaz, 2020, Extracellular Vesicles Derived From Mesenchymal Stem Cells (MSC) in Regenerative Medicine: Applications in Skin Wound Healing, Front Bioeng Biotechnol, 8, 1, 10.3389/fbioe.2020.00146 · DOI
  22. Hoang, 2020, Differential Wound Healing Capacity of Mesenchymal Stem Cell-Derived Exosomes Originated From Bone Marrow, Adipose Tissue and Umbilical Cord Under Serum- and Xeno-Free Condition, Front Mol Biosci, 7, 10.3389/fmolb.2020.00119 · DOI
  23. Wu, 2018, MSC-exosome: A novel cell-free therapy for cutaneous regeneration, Cytotherapy, 20, 291, 10.1016/j.jcyt.2017.11.002 · DOI
  24. Shi, 2019, Mesenchymal stem cell–derived extracellular vesicles: a new impetus of promoting angiogenesis in tissue regeneration, Cytotherapy, 21, 497, 10.1016/j.jcyt.2018.11.012 · DOI
  25. Lai, 2010, Exosome secreted by MSC reduces myocardial ischemia/reperfusion injury, Stem Cell Res, 4, 214, 10.1016/j.scr.2009.12.003 · DOI · Paper page
  26. Zhang, 2016, Pretreatment of Cardiac Stem Cells With Exosomes Derived From Mesenchymal Stem Cells Enhances Myocardial Repair, J Am Heart Assoc, 5, 10.1161/JAHA.115.002856 · DOI
  27. Cosenza, 2018, Mesenchymal stem cells-derived exosomes are more immunosuppressive than microparticles in inflammatory arthritis, Theranostics, 8, 1399, 10.7150/thno.21072 · DOI
  28. Li, 2013, Exosomes Derived from Human Umbilical Cord Mesenchymal Stem Cells Alleviate Liver Fibrosis, Stem Cells Dev, 22, 845, 10.1089/scd.2012.0395 · DOI
  29. Zhang B, Wang M, Gong A, Zhang X, Wu X, Zhu Y, et al. HucMSC-Exosome Mediated-Wnt4 Signaling Is Required for Cutaneous Wound Healing. Stem Cells 2015;33:2158–68. https://doi.org/10.1002/stem.1771. · DOI
  30. Zhang, 2015, Exosomes released from human induced pluripotent stem cells-derived MSCs facilitate cutaneous wound healing by promoting collagen synthesis and angiogenesis, J Transl Med, 13, 10.1186/s12967-015-0417-0 · DOI
  31. Shabbir, 2015, Mesenchymal Stem Cell Exosomes Induce Proliferation and Migration of Normal and Chronic Wound Fibroblasts, and Enhance Angiogenesis In Vitro, Stem Cells Dev, 24, 1635, 10.1089/scd.2014.0316 · DOI
  32. Mardpour, 2019, Interaction between mesenchymal stromal cell-derived extracellular vesicles and immune cells by distinct protein content, J Cell Physiol, 234, 8249, 10.1002/jcp.27669 · DOI
  33. Gursel, 2003, Repetitive Elements in Mammalian Telomeres Suppress Bacterial DNA-Induced Immune Activation, J Immunol, 171, 1393, 10.4049/jimmunol.171.3.1393 · DOI
  34. Shirota, 2004, Suppressive Oligodeoxynucleotides Inhibit Th1 Differentiation by Blocking IFN-γ- and IL-12-Mediated Signaling, J Immunol, 173, 5002, 10.4049/jimmunol.173.8.5002 · DOI
  35. Kaminski, 2013, Synthetic Oligodeoxynucleotides Containing Suppressive TTAGGG Motifs Inhibit AIM2 Inflammasome Activation, J Immunol, 191, 3876, 10.4049/jimmunol.1300530 · DOI · Paper page
  36. Yazar V, Kilic G, Bulut O, Canavar Yildirim T, Yagci FC, Aykut G, et al. A suppressive oligodeoxynucleotide expressing TTAGGG motifs modulates cellular energetics through the mTOR signaling pathway. Int Immunol 2020;32:39–48. https://doi.org/10.1093/intimm/dxz059. · DOI
  37. Martins, 2014, Towards an advanced therapy medicinal product based on mesenchymal stromal cells isolated from the umbilical cord tissue: quality and safety data, Stem Cell Res Ther, 5, 10.1186/scrt398 · DOI
  38. Gursel M, Gursel I. Development of CpG ODN Based Vaccine Adjuvant Formulations. In: Thomas S, editor. Vaccine Des. Methods Protoc. Vol. 2 Vaccines Vet. Dis., vol. 1404, New York, NY: Springer New York; 2016, p. 289–98. https://doi.org/10.1007/978-1-4939-3389-1_20. · DOI
  39. Perez-Riverol Y, Csordas A, Bai J, Bernal-Llinares M, Hewapathirana S, Kundu DJ, et al. The PRIDE database and related tools and resources in 2019: improving support for quantification data. Nucleic Acids Res 2019;47:D442–50. https://doi.org/10.1093/nar/gky1106. · DOI
  40. Miranda, 2006, Development of a recombinant indirect ELISA for the diagnosis of Theileria sp. (China) infection in small ruminants, Parasitol Res, 98, 561, 10.1007/s00436-005-0105-8 · DOI
  41. Danaei, 2018, Impact of Particle Size and Polydispersity Index on the Clinical Applications of Lipidic Nanocarrier Systems, Pharmaceutics, 10, 57, 10.3390/pharmaceutics10020057 · DOI
  42. Andreu, 2014, Tetraspanins in extracellular vesicle formation and function, Front Immunol, 5, 442, 10.3389/fimmu.2014.00442 · DOI
  43. Gunawardena, 2019, Conditioned media derived from mesenchymal stem cell cultures: The next generation for regenerative medicine, J Tissue Eng Regen Med, 13, 569, 10.1002/term.2806 · DOI
  44. Konala, 2016, The current landscape of the mesenchymal stromal cell secretome: A new paradigm for cell-free regeneration, Cytotherapy, 18, 13, 10.1016/j.jcyt.2015.10.008 · DOI
  45. Ferreira, 2018, Mesenchymal stromal cell secretome: Influencing therapeutic potential by cellular pre-conditioning, Front Immunol, 9, 1, 10.3389/fimmu.2018.02837 · DOI · Paper page
  46. Liu, 2016, Short-term memory of danger signals or environmental stimuli in mesenchymal stem cells: implications for therapeutic potential, Cell Mol Immunol, 13, 369, 10.1038/cmi.2015.11 · DOI
  47. EL Andaloussi, 2013, Extracellular vesicles: biology and emerging therapeutic opportunities, Nat Rev Drug Discov, 12, 347, 10.1038/nrd3978 · DOI · Paper page
  48. Hu, 2016, Exosomes derived from human adipose mensenchymal stem cells accelerates cutaneous wound healing via optimizing the characteristics of fibroblasts, Sci Rep, 6
  49. Fang S, Xu C, Zhang Y, Xue C, Yang C, Bi H, et al. Umbilical Cord-Derived Mesenchymal Stem Cell-Derived Exosomal MicroRNAs Suppress Myofibroblast Differentiation by Inhibiting the Transforming Growth Factor-β/SMAD2 Pathway During Wound Healing. Stem Cells Transl Med 2016;5:1425–39. https://doi.org/10.5966/sctm.2015-0367. · DOI
  50. Wang, 2019, Fetal Dermal Mesenchymal Stem Cell-Derived Exosomes Accelerate Cutaneous Wound Healing by Activating Notch Signaling, Stem Cells Int, 2019, 1, 10.1155/2019/6568394 · DOI
  51. Frith, 2010, Dynamic Three-Dimensional Culture Methods Enhance Mesenchymal Stem Cell Properties and Increase Therapeutic Potential, Tissue Eng Part C Methods, 16, 735, 10.1089/ten.tec.2009.0432 · DOI
  52. Bartosh, 2010, Aggregation of human mesenchymal stromal cells (MSCs) into 3D spheroids enhances their antiinflammatory properties, Proc Natl Acad Sci, 107, 13724, 10.1073/pnas.1008117107 · DOI
  53. Potapova, 2008, Culturing of Human Mesenchymal Stem Cells as Three-dimensional Aggregates Induces Functional Expression of CXCR4 That Regulates Adhesion to Endothelial Cells, J Biol Chem, 283, 13100, 10.1074/jbc.M800184200 · DOI
  54. YlÖstalo, 2012, Human Mesenchymal Stem/Stromal Cells Cultured as Spheroids are Self-activated to Produce Prostaglandin E2 that Directs Stimulated Macrophages into an Anti-inflammatory Phenotype, Stem Cells, 30, 2283, 10.1002/stem.1191 · DOI · Paper page
  55. Gallucci, 2001, Interleukin-6 Treatment Augments Cutaneous Wound Healing in Immunosuppressed Mice, J Interf Cytokine Res, 21, 603, 10.1089/10799900152547867 · DOI
  56. Lin, 2003, Essential involvement of IL-6 in the skin wound-healing process as evidenced by delayed wound healing in IL-6-deficient mice, J Leukoc Biol, 73, 713, 10.1189/jlb.0802397 · DOI · Paper page
  57. Liechty, 2000, Diminished interleukin 6 (IL-6) production during scarless human fetal wound repair, Cytokine, 12, 671, 10.1006/cyto.1999.0598 · DOI
  58. Yew, 2011, Enhancement of Wound Healing by Human Multipotent Stromal Cell Conditioned Medium: The Paracrine Factors and p38 MAPK Activation, Cell Transplant, 20, 693, 10.3727/096368910X550198 · DOI
  59. Behm, 2012, Cytokines, chemokines and growth factors in wound healing, J Eur Acad Dermatol Venereol, 26, 812, 10.1111/j.1468-3083.2011.04415.x · DOI
  60. Eming, 2014, Wound repair and regeneration: Mechanisms, signaling, and translation, Sci Transl Med, 6, 10.1126/scitranslmed.3009337 · DOI · Paper page
  61. Barrientos, 2008, Growth factors and cytokines in wound healing, Wound Repair Regen, 16, 585, 10.1111/j.1524-475X.2008.00410.x · DOI · Paper page
  62. King, 2014, Regenerative Wound Healing: The Role of Interleukin-10, Adv Wound Care, 3, 315, 10.1089/wound.2013.0461 · DOI
  63. Luo, 2005, Nitric oxide: a newly discovered function on wound healing, Acta Pharmacol Sin, 26, 259, 10.1111/j.1745-7254.2005.00058.x · DOI
  64. Wood, 2014, Pro-inflammatory chemokine CCL2 (MCP-1) promotes healing in diabetic wounds by restoring the macrophage response, PLoS ONE, 9, e91574, 10.1371/journal.pone.0091574 · DOI
  65. Ashcroft, 2012, Tumor necrosis factor-alpha (TNF-α) is a therapeutic target for impaired cutaneous wound healing, Wound Repair Regen, 20, 38, 10.1111/j.1524-475X.2011.00748.x · DOI
  66. Huang, 2019, High glucose environment induces M1 macrophage polarization that impairs keratinocyte migration via TNF-α: An important mechanism to delay the diabetic wound healing, J Dermatol Sci, 96, 159, 10.1016/j.jdermsci.2019.11.004 · DOI
  67. Ou, 2015, Kruppel-like factor KLF4 facilitates cutaneous wound healing by promoting fibrocyte generation from myeloid-derived suppressor cells, J Invest Dermatol, 135, 1425, 10.1038/jid.2015.3 · DOI

Cited by

Sorted by citations

  • Mesenchymal stem cell secretome for regenerative medicine: Where do we stand?

    Trigo, C. M., Rodrigues, J. S., Camões, S. P., Solá, S., & Miranda, J. P. (2025) · Journal of Advanced Research · doi:10.1016/j.jare.2024.05.004 · Cited by 252

    “Nevertheless, the anti-inflammatory and immunomodulatory capacities of MSCs (Table 1) were postulated as essential to retrieve local and systemic conditions for normal tissue repair alongside MSC-mediated pro-angiogenic, anti-apoptotic and antimicrobial effects (Table 2) [8,9,12,39,42,43].”
    Self-citation

Metadata

Authors
Camões, S. P., Bulut, O., Yazar, V., Gaspar, M. M., Simões, S., Ferreira, R., Vitorino, R., Santos, J. M., Gursel, I., & Miranda, J. P.
Affiliations
  • University of Lisbon (PT)
  • Bilkent University (TR)
  • Johns Hopkins University (US)
  • University of Aveiro (PT)
  • Universidade do Porto (PT)
  • Universidade Nova de Lisboa (PT)
Corresponding author
Miranda, Joana P.
ORCID
Venue
Journal of Advanced Research
Publisher
Elsevier BV
Published
2022-11
Volume
41
Pages
113-128
ISSN
  • 2090-1224 (ISSN-L)
  • 2090-1232
DOI
10.1016/j.jare.2022.01.013
PMC
PMC9637564
OpenAlex
W4210628040
Cited by
55
References
4
Citations by year
2026: 10 · 2025: 18 · 2024: 11 · 2023: 12 · 2022: 4
FWCI
3.67
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Advanced Research (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Portuguese National Funding Agency for Science, Research and Technology (RCAAP Project by FCT) (submittedVersion, other-oa)
  • Bilkent University Institutional Repository (Bilkent University) (submittedVersion)
Funders
  • European Commission (POCI-01-0145-FEDER-007628)
  • COST (CA16113, CA16119)
  • Fundação para a Ciência e a Tecnologia (PTDC/MED-QUI/31721/2017, PTDC/MED-TOX/29183/2017, PTDC/SAU-SER/30197/2017, UID/00051/2020, UID/BIM/04501/2020, UIDB/04138/2020, UIDP/04138/2020)
  • European Regional Development Fund
  • Programa Operacional Temático Factores de Competitividade
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Extracellular vesicles in disease
  • Health Sciences › Medicine › Surgery › Wound Healing and Treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Mesenchymal stem cell research
Keywords
mesenchymal stem cell-derived exosomes, 3D cell culture, skin wound healing, chronic wounds, immunomodulation, exosomal proteome, re-epithelialization, granulation tissue, inflammatory cytokines, interleukin-6, TNF-α
MeSH terms
Immunity, Tumor Necrosis Factor-alpha, Interleukin-6, Transforming Growth Factor beta, Proteomics, Exosomes

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review