1. Shi, Y. et al. Immunoregulatory mechanisms of mesenchymal stem and stromal cells in infammatory diseases. Nat. Rev. Nephrol. 14, 493–507 (2018).
2. Park, W. S., Ahn, S. Y., Sung, S. I., Ahn, J. Y. & Chang, Y. S. Strategies to enhance paracrine potency of transplanted mesenchymal stem cells in intractable neonatal disorders. Pediatr. Res. 83, 214–222 (2018).
3. Uccelli, A., Moretta, L. & Pistoia, V. Mesenchymal stem cells in health and disease. Nat. Rev. Immunol. 8, 726–736 (2008).
4. Fan, X. L., Zhang, Y., Li, X. & Fu, Q. L. Mechanisms underlying the protective efects of mesenchymal stem cell-based therapy. Cell. Mol. Life Sci. 77, 2771–2794 (2020).
5. Phinney, D. G. & Pittenger, M. F. Concise review: MSC-derived exosomes for cell-free therapy. Stem Cells 35, 851–858 (2017).
6. Phinney, D. G. et al. Mesenchymal stem cells use extracellular vesicles to outsource mitophagy and shuttle microRNAs. Nat. Commun. 6, 8472 (2015).
7. Mills, C. D., Kincaid, K., Alt, J. M., Heilman, M. J. & Hill, A. M. M-1/M-2 macrophages and the T1/T2 paradigm. J. Immunol. 164, 6166–6173 (2000).
8. Gordon, S. & Martinez, F. O. Alternative activation of macrophages: Mechanism and functions. Immunity 32, 593–604 (2010).
9. Roberts, V. S., Cowan, P. J., Alexander, S. I., Robson, S. C. & Dwyer, K. M. Te role of adenosine receptors A2A and A2B signaling in renal fbrosis. Kidney Int. 86, 685–692 (2014).
10. Hasko, G. & Cronstein, B. Regulation of infammation by adenosine. Front. Immunol. 4, 85 (2013).
11. Cohen, H. B. et al. TLR stimulation initiates a CD39-based autoregulatory mechanism that limits macrophage infammatory responses. Blood 122, 1935–1945 (2013).
12. Ferrante, C. J. et al. Te adenosine-dependent angiogenic switch of macrophages to an M2-like phenotype is independent of interleukin-4 receptor alpha (IL-4Rα) signaling. Infammation 36, 921–931 (2013).
13. Stevens, H. Y., Bowles, A. C., Yeago, C. & Roy, K. Molecular crosstalk between macrophages and mesenchymal stromal cells. Front. Cell Dev. Biol. 8, 600160 (2020).
14. Mantovani, A., Biswas, S. K., Galdiero, M. R., Sica, A. & Locati, M. Macrophage plasticity and polarization in tissue repair and remodelling. J. Pathol. 229, 176–185 (2013).
15. Wang, J. et al. Mesenchymal stem cell-derived extracellular vesicles alter disease outcomes via endorsement of macrophage polarization. Stem Cell Res. Ter. 11, 424 (2020).
16. Nakao, Y. et al. Exosomes from TNF-α-treated human gingiva-derived MSCs enhance M2 macrophage polarization and inhibit periodontal bone loss. Acta Biomater. 122, 306–324 (2021).
17. Katsuda, T., Kosaka, N., Takeshita, F. & Ochiya, T. Te therapeutic potential of mesenchymal stem cell-derived extracellular vesicles. Proteomics 13, 1637–1653 (2013).
18. El Moshy, S. et al. Dental stem cell-derived secretome/conditioned medium: Te future for regenerative therapeutic applications. Stem Cells Int. 2020, 7593402 (2020).
19. Kim, D., Lee, A. E., Xu, Q., Zhang, Q. & Le, A. D. Gingiva-derived mesenchymal stem cells: Potential application in tissue engineering and regenerative medicine—A comprehensive review. Front. Immunol. 12, 667221 (2021).
20. Kou, X. et al. Te Fas/Fap-1/Cav-1 complex regulates IL-1RA secretion in mesenchymal stem cells to accelerate wound healing. Sci. Transl. Med. https://doi.org/10.1126/scitranslmed.aai8524 (2018).
21. Opitz, C. A. et al. Toll-like receptor engagement enhances the immunosuppressive properties of human bone marrow-derived mesenchymal stem cells by inducing indoleamine-2,3-dioxygenase-1 via interferon-beta and protein kinase R. Stem Cells 27, 909–919 (2009).
22. Lin, T. et al. Preconditioning of murine mesenchymal stem cells synergistically enhanced immunomodulation and osteogenesis. Stem Cell Res. Ter. 8, 277 (2017).
23. Boland, L. et al. IFN-γ and TNF-α pre-licensing protects mesenchymal stromal cells from the pro-infammatory efects of palmitate. Mol. Ter. 26, 860–873 (2018).
24. Niemelä, J. et al. IFN-alpha induced adenosine production on the endothelium: A mechanism mediated by CD73 (ecto-5’-nucleotidase) up-regulation. J. Immunol. 172, 1646–1653 (2004).
25. Gusella, G. L., Musso, T., Rottschafer, S. E., Pulkki, K. & Varesio, L. Potential requirement of a functional double-stranded RNAdependent protein kinase (PKR) for the tumoricidal activation of macrophages by lipopolysaccharide or IFN-alpha beta, but not IFN-gamma. J. Immunol. 154, 345–354 (1995).
26. Suzuki, S. et al. Dental pulp cell-derived powerful inducer of TNF-α comprises PKR containing stress granule rich microvesicles. Sci. Rep. 9, 3825 (2019).
27. Wouters, B. G. & Koritzinsky, M. Hypoxia signalling through mTOR and the unfolded protein response in cancer. Nat. Rev. Cancer 8, 851–864 (2008).
28. Mindaye, S. T., Ra, M., Lo Surdo, J., Bauer, S. R. & Alterman, M. A. Improved proteomic profling of the cell surface of cultureexpanded human bone marrow multipotent stromal cells. J. Proteom. 78, 1–14 (2013).
29. Sanjurjo, L. et al. CD5L promotes M2 macrophage polarization through autophagy-mediated upregulation of ID3. Front. Immunol. 9, 480 (2018).
30. Joseph, S. B. et al. LXR-dependent gene expression is important for macrophage survival and the innate immune response. Cell 119, 299–309 (2004).
31. Li, J. et al. Serum-free culture alters the quantity and protein composition of neuroblastoma-derived extracellular vesicles. J. Extracell. Vesicles 4, 26883 (2015).
32. Oskowitz, A., McFerrin, H., Gutschow, M., Carter, M. L. & Pochampally, R. Serum-deprived human multipotent mesenchymal stromal cells (MSCs) are highly angiogenic. Stem Cell Res. 6, 215–225 (2011).
33. Ando, Y. et al. Stem cell-conditioned medium accelerates distraction osteogenesis through multiple regenerative mechanisms. Bone 61, 82–90 (2014).
34. Yuan, O. et al. Exosomes derived from human primed mesenchymal stem cells induce mitosis and potentiate growth factor secretion. Stem Cells Dev. 28, 398–409 (2019).
35. Elahi, F. M., Farwell, D. G., Nolta, J. A. & Anderson, J. D. Preclinical translation of exosomes derived from mesenchymal stem/ stromal cells. Stem Cells 38, 15–21 (2020).
36. Le Blanc, K. & Mougiakakos, D. Multipotent mesenchymal stromal cells and the innate immune system. Nat. Rev. Immunol. 12, 383–396 (2012).
37. Madrigal, M., Rao, K. S. & Riordan, N. H. A review of therapeutic efects of mesenchymal stem cell secretions and induction of secretory modifcation by diferent culture methods. J. Transl. Med. 12, 260 (2014).
38. López-García, L. & Castro-Manrreza, M. E. TNF-α and IFN-γ participate in improving the immunoregulatory capacity of mesenchymal stem/stromal cells: Importance of cell–cell contact and extracellular vesicles. Int. J. Mol. Sci. 22, 9531 (2021).
39. Saldaña, L. et al. Immunoregulatory potential of mesenchymal stem cells following activation by macrophage-derived soluble factors. Stem Cell Res. Ter. 10, 58 (2019).
40. Yu, Y. et al. Preconditioning with interleukin-1 beta and interferon-gamma enhances the efcacy of human umbilical cord bloodderived mesenchymal stem cells-based therapy via enhancing prostaglandin E2 secretion and indoleamine 2,3-dioxygenase activity in dextran sulfate sodium-induced colitis. J. Tissue Eng. Regen. Med. 13, 1792–1804 (2019).
41. Pagnotta, S. M. et al. Ensemble of gene signatures identifes novel biomarkers in colorectal cancer activated through PPARγ and TNFα signaling. PLoS ONE 8, e72638 (2013).
42. Kordaß, T., Osen, W. & Eichmüller, S. B. Controlling the immune suppressor: Transcription factors and microRNAs regulating CD73/NT5E. Front. Immunol. 9, 813 (2018).
43. Synnestvedt, K. et al. Ecto-5’-nucleotidase (CD73) regulation by hypoxia-inducible factor-1 mediates permeability changes in intestinal epithelia. J. Clin. Investig. 110, 993–1002 (2002).
44. Malkov, M. I., Lee, C. T. & Taylor, C. T. Regulation of the hypoxia-inducible factor (HIF) by pro-infammatory cytokines. Cells 10, 2340 (2021).
45. Gerber, S. A. & Pober, J. S. IFN-alpha induces transcription of hypoxia-inducible factor-1alpha to inhibit proliferation of human endothelial cells. J. Immunol. 181, 1052–1062 (2008).
46. Land, S. C. & Tee, A. R. Hypoxia-inducible factor 1alpha is regulated by the mammalian target of rapamycin (mTOR) via an mTOR signaling motif. J. Biol. Chem. 282, 20534–20543 (2007).
47. Lee, D. F. et al. IKK beta suppression of TSC1 links infammation and tumor angiogenesis via the mTOR pathway. Cell 130, 440–455 (2007).
48. Pai, R. L. et al. Type I IFN response associated with mTOR activation in the TAFRO subtype of idiopathic multicentric Castleman disease. JCI Insight https://doi.org/10.1172/jci.insight.135031 (2020).
49. Noronha, N. C. et al. Priming approaches to improve the efcacy of mesenchymal stromal cell-based therapies. Stem Cell Res. Ter. 10, 131 (2019).
50. Sanjurjo, L., Aran, G., Roher, N., Valledor, A. F. & Sarrias, M. R. AIM/CD5L: A key protein in the control of immune homeostasis and infammatory disease. J. Leukoc. Biol. 98, 173–184 (2015).
51. Sanjurjo, L. et al. Te human CD5L/AIM-CD36 axis: A novel autophagy inducer in macrophages that modulates infammatory responses. Autophagy 11, 487–502 (2015).
52. Ge, L. et al. Secretome of olfactory mucosa mesenchymal stem cell, a multiple potential stem cell. Stem Cells Int. 2016, 1243659 (2016).
53. Mathivanan, S. & Simpson, R. J. ExoCarta: A compendium of exosomal proteins and RNA. Proteomics 9, 4997–5000 (2009).
54. Valledor, A. F. et al. Activation of liver X receptors and retinoid X receptors prevents bacterial-induced macrophage apoptosis. Proc. Natl. Acad. Sci. U.S.A. 101, 17813–17818 (2004).
55. Yan, J. & Horng, T. Lipid metabolism in regulation of macrophage functions. Trends Cell Biol. 30, 979–989 (2020).
56. Shapouri-Moghaddam, A. et al. Macrophage plasticity, polarization, and function in health and disease. J. Cell. Physiol. 233, 6425–6440 (2018).
57. Zhang, Q. et al. Mesenchymal stem cells derived from human gingiva are capable of immunomodulatory functions and ameliorate infammation-related tissue destruction in experimental colitis. J. Immunol. 183, 7787–7798 (2009).
58. Zhang, Q. Z. et al. Human gingiva-derived mesenchymal stem cells elicit polarization of m2 macrophages and enhance cutaneous wound healing. Stem Cells 28, 1856–1868 (2010).
59. Téry, C. et al. Minimal information for studies of extracellular vesicles 2018 (MISEV2018): A position statement of the International Society for Extracellular Vesicles and update of the MISEV2014 guidelines. J. Extracell. Vesicles 7, 1535750 (2018).
60. Nakai, W. et al. A novel afnity-based method for the isolation of highly purifed extracellular vesicles. Sci. Rep. 6, 33935 (2016).
61. Toyoda, K. et al. Grp78 is critical for amelogenin-induced cell migration in a multipotent clonal human periodontal ligament cell line. J. Cell Physiol. 231, 414–427 (2016).