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Synergy and translation of allogenic bone marrow stem cells after photodynamic treatment of rheumatoid arthritis with tetra sulfonatophenyl porphyrin and TiO2 nanowhiskers

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Abstract

Rheumatoid arthritis (RA) etiology and amelioration remains a challenge in modern therapeutics. Herein, we explored the synergistic effect of allogenic bone marrow stem cell (BMSC) translation and photodynamic treatment of RA with tetra sulfonatophenyl porphyrin (TSPP) and TiO2 nanocomposites as a new strategy for RA theranostics. The translation of BMSCs with miRNAs into infected joints in long bones post-photodynamic therapy is helpful for treating and understanding RA pathophysiology. We observed that allogenic BMSC translation combined with TSPP-TiO2 nanocomposites can significantly (p < 0.01) lower the concentrations of serum biomarkers (tumor necrosis factor-α and interleukin-17) in a collagen induced arthritis (CIA) murine model, both in vitro and in vivo, as well as improve other parameters such as arthritis score, BMSC count, complete blood count, and numbers of platelets, red blood cells, and white blood cells. Moreover, a fluorescent TSPP in the feet or long bones and X-ray bioimaging of RA joints revealed the clinical efficacy of BMSCs combined with TSPP-TiO2 nanocomposites. Microarray data analysis illustrated that rno-mir-375-3p and rno-mir-196b-3p were up-regulated by approximately 100-fold in the BMSCs of ameliorated RA post-photodynamic therapy with TSPP-TiO2 nanocomposites. Our study not only suggests a new approach for RA theranostics, but also helps in understanding RA pathophysiology.

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References

  1. United Nations. Prevention and control of non-communicable diseases. Report of the Secretary-General. New York: United Nations, 2011.

    Google Scholar 

  2. Schuna, A. A. Update on treatment of rheumatoid arthritis. J. Am. Pharm. Assoc. (Wash.) 1998, 38, 728–735; quiz 735–737.

    Article  Google Scholar 

  3. Rudan, I.; Sidhu, S.; Papana, A.; Meng, S. J.; Xin–Wei, Y.; Wang, W.; Campbell–Page, R. M.; Demaio, A. R.; Nair, H.; Sridhar, D. et al. Prevalence of rheumatoid arthritis in low-and middle-income countries: A systematic review and analysis. J. Glob. Health 2015, 5, 010409.

    Article  Google Scholar 

  4. Firestein, G. S. Evolving concepts of rheumatoid arthritis. Nature 2003, 423, 356–361.

    Article  Google Scholar 

  5. Chen, L. J.; Bao, B.; Wang, N. P.; Xie, J.; Wu, W. H. Oral administration of shark type II collagen suppresses complete Freund’s adjuvant-induced rheumatoid arthritis in rats. Pharmaceuticals 2012, 5, 339–352.

    Article  Google Scholar 

  6. Brennan, F. M.; Maini, R. N.; Feldmann, M. TNFα—A pivotal role in rheumatoid arthritis? Rheumatology 1992, 31, 293–298.

    Article  Google Scholar 

  7. Chabaud, M.; Durand, J. M.; Buchs, N.; Fossiez, F.; Page, G.; Frappart, L.; Miossec, P. Human interleukin-17: A T cell-derived proinflammatory cytokine produced by the rheumatoid synovium. Arthritis Rheum. 1999, 42, 963–970.

    Article  Google Scholar 

  8. Ziolkowska, M.; Koc, A.; Luszczykiewicz, G.; Ksiezopolska-Pietrzak, K.; Klimczak, E.; Chwalinska-Sadowska, H.; Maslinski, W. High levels of IL-17 in rheumatoid arthritis patients: IL-15 triggers in vitro IL-17 production via cyclosporin A-sensitive mechanism. J. Immunol. 2000, 164, 2832–2838.

    Article  Google Scholar 

  9. Grove, J. E.; Bruscia, E.; Krause, D. S. Plasticity of bone marrow-derived stem cells. Stem Cells 2004, 22, 487–500.

    Article  Google Scholar 

  10. Taichman, R. S. Blood and bone: Two tissues whose fates are intertwined to create the hematopoietic stem-cell niche. Blood 2005, 105, 2631–2639.

    Article  Google Scholar 

  11. Zappia, E.; Casazza, S.; Pedemonte, E.; Benvenuto, F.; Bonanni, I.; Gerdoni, E.; Giunti, D.; Ceravolo, A.; Cazzanti, F.; Frassoni, F. et al. Mesenchymal stem cells ameliorate experimental autoimmune encephalomyelitis inducing T-cell anergy. Blood 2005, 106, 1755–1761.

    Article  Google Scholar 

  12. Liu, C.-H.; Hwang, S.-M. Cytokine interactions in mesenchymal stem cells from cord blood. Cytokine 2005, 32, 270–279.

    Article  Google Scholar 

  13. Maitra, B.; Szekely, E.; Gjini, K.; Laughlin, M. J.; Dennis, J.; Haynesworth, S. E.; Koc, O. N. Human mesenchymal stem cells support unrelated donor hematopoietic stem cells and suppress T-cell activation. Bone Marrow Transplant. 2004, 33, 597–604.

    Article  Google Scholar 

  14. Potian, J. A.; Aviv, H.; Ponzio, N. M.; Harrison, J. S.; Rameshwar, P. Veto-like activity of mesenchymal stem cells: Functional discrimination between cellular responses to alloantigens and recall antigens. J. Immunol. 2003, 171, 3426–3434.

    Article  Google Scholar 

  15. Di Nicola, M.; Carlo-Stella, C.; Magni, M.; Milanesi, M.; Longoni, P. D.; Matteucci, P.; Grisanti, S.; Gianni, A. M. Human bone marrow stromal cells suppress T-lymphocyte proliferation induced by cellular or nonspecific mitogenic stimuli. Blood 2002, 99, 3838–3843.

    Article  Google Scholar 

  16. Yoshida, Y.; Takahashi, K.; Okita, K.; Ichisaka, T.; Yamanaka, S. Hypoxia enhances the generation of induced pluripotent stem cells. Cell Stem Cell 2009, 5, 237–241.

    Article  Google Scholar 

  17. Bartel, D. P. MicroRNAs: Genomics, biogenesis, mechanism, and function. Cell 2004, 116, 281–297.

    Article  Google Scholar 

  18. He, L.; He, X. Y.; Lowe, S. W.; Hannon, G. J. MicroRNAs join the p53 network—Another piece in the tumoursuppression puzzle. Nat. Rev. Cancer 2007, 7, 819–822.

    Article  Google Scholar 

  19. Esau, C.; Davis, S.; Murray, S. F.; Yu, X. X.; Pandey, S. K.; Pear, M.; Watts, L.; Booten, S. L.; Graham, M.; McKay, R. et al. miR-122 regulation of lipid metabolism revealed by in vivo antisense targeting. Cell Metab. 2006, 3, 87–98.

    Article  Google Scholar 

  20. Chen, C.-Z.; Li, L.; Lodish, H. F.; Bartel, D. P. MicroRNAs modulate hematopoietic lineage differentiation. Science 2004, 303, 83–86.

    Article  Google Scholar 

  21. Callis, T. E.; Chen, J.-F.; Wang, D.-Z. MicroRNAs in skeletal and cardiac muscle development. DNA Cell Biol. 2007, 26, 219–225.

    Article  Google Scholar 

  22. Calin, G. A.; Ferracin, M.; Cimmino, A.; Di Leva, G.; Shimizu, M.; Wojcik, S. E.; Iorio, M. V.; Visone, R.; Sever, N. I.; Fabbri, M. et al. A microRNA signature associated with prognosis and progression in chronic lymphocytic leukemia. N. Engl. J. Med. 2005, 353, 1793–1801.

    Article  Google Scholar 

  23. Hanson, E. K.; Lubenow, H.; Ballantyne, J. Identification of forensically relevant body fluids using a panel of differentially expressed microRNAs. Anal. Biochem. 2009, 387, 303–314.

    Article  Google Scholar 

  24. Mitchell, P. S.; Parkin, R. K.; Kroh, E. M.; Fritz, B. R.; Wyman, S. K.; Pogosova-Agadjanyan, E. L.; Peterson, A.; Noteboom, J.; O'Briant, K. C.; Allen, A. et al. Circulating microRNAs as stable blood-based markers for cancer detection. Proc. Natl. Acad. Sci. USA 2008, 105, 10513–10518.

    Article  Google Scholar 

  25. Stanczyk, J.; Pedrioli, D. M. L.; Brentano, F.; Sanchez-Pernaute, O.; Kolling, C.; Gay, R. E.; Detmar, M.; Gay, S.; Kyburz, D. Altered expression of microRNA in synovial fibroblasts and synovial tissue in rheumatoid arthritis. Arthritis Rheum. 2008, 58, 1001–1009.

    Article  Google Scholar 

  26. Nakamachi, Y.; Kawano, S.; Takenokuchi, M.; Nishimura, K.; Sakai, Y.; Chin, T.; Saura, R.; Kurosaka, M.; Kumagai, S. MicroRNA-124a is a key regulator of proliferation and monocyte chemoattractant protein 1 secretion in fibroblastlike synoviocytes from patients with rheumatoid arthritis. Arthritis Rheum. 2009, 60, 1294–1304.

    Article  Google Scholar 

  27. Dougherty, T. J.; Gomer, C. J.; Henderson, B. W.; Jori, G.; Kessel, D.; Korbelik, M.; Moan, J.; Peng, Q. Photodynamic therapy. J. Natl. Cancer Inst. 1998, 90, 889–905.

    Article  Google Scholar 

  28. Lucky, S. S.; Soo, K. C.; Zhang, Y. Nanoparticles in photodynamic therapy. Chem. Rev. 2015, 115, 1990–2042.

    Article  Google Scholar 

  29. Zhao, C. Q.; Ur Rehman, F.; Yang, Y. L.; Li, X. Q.; Zhang, D.; Jiang, H.; Selke, M.; Wang, X. M.; Liu, C. Y. Bio-imaging and photodynamic therapy with tetra sulphonatophenyl porphyrin (TSPP)-TiO2 nanowhiskers: New approaches in rheumatoid arthritis theranostics. Sci. Rep. 2015, 5, 11518.

    Article  Google Scholar 

  30. Rehman, F. U.; Zhao, C. Q.; Wu, C. Y.; Jiang, H.; Selke, M.; Wang, X. M. Influence of photoactivated tetra sulphonatophenyl porphyrin and TiO2 nanowhiskers on rheumatoid arthritis infected bone marrow stem cell proliferation in vitro and oxidative stress biomarkers in vivo. RSC Adv. 2015, 5, 107285–107292.

    Article  Google Scholar 

  31. Benov, L.; Batinic-Haberle, I. A manganese porphyrin suppresses oxidative stress and extends the life span of streptozotocin-diabetic rats. Free Radic. Res. 2005, 39, 81–88.

    Article  Google Scholar 

  32. Chu, Z. Q.; Zhang, S.; Yin, C.; Lin, G.; Li, Q. Designing nanoparticle carriers for enhanced drug efficacy in photodynamic therapy. Biomater. Sci. 2014, 2, 827–832.

    Article  Google Scholar 

  33. Rehman, F. U.; Zhao, C. Q.; Jiang, H.; Selke, M.; Wang, X. M. Protective effect of TiO2 nanowhiskers on tetra sulphonatophenyl porphyrin (TSPP) complexes induced oxidative stress during photodynamic therapy. Photodiagnosis Photodyn. Ther. 2016, 13, 267–275.

    Article  Google Scholar 

  34. Cai, R. X.; Hashimoto, K.; Itoh, K.; Kubota, Y.; Fujishima, A. Photokilling of malignant cells with ultrafine TiO2 powder. Bull. Chem. Soc. Jpn. 1991, 64, 1268–1273.

    Article  Google Scholar 

  35. Rehman, F. U.; Zhao, C.; Jiang, H.; Wang, X. Biomedical applications of nano-titania in theranostics and photodynamic therapy. Biomater. Sci. 2016, 4, 40–54.

    Article  Google Scholar 

  36. Zhang, S. C.; Yang, D. J.; Jing, D. W.; Liu, H. W.; Liu, L.; Jia, Y.; Gao, M. H.; Guo, L. J.; Huo, Z. Y. Enhanced photodynamic therapy of mixed phase TiO2(B)/anatase nanofibers for killing of HeLa cells. Nano Res. 2014, 7, 1659–1669.

    Article  Google Scholar 

  37. Jimenez-Boj, E.; Redlich, K.; Türk, B.; Hanslik-Schnabel, B.; Wanivenhaus, A.; Chott, A.; Smolen, J. S.; Schett, G. Interaction between synovial inflammatory tissue and bone marrow in rheumatoid arthritis. J. Immunol. 2005, 175, 2579–2588.

    Article  Google Scholar 

  38. Sekiya, I.; Larson, B. L.; Smith, J. R.; Pochampally, R.; Cui, J. G.; Prockop, D. J. Expansion of human adult stem cells from bone marrow stroma: Conditions that maximize the yields of early progenitors and evaluate their quality. Stem Cells 2002, 20, 530–541.

    Article  Google Scholar 

  39. De Jong, W. H.; Borm, P. J. Drug delivery and nanoparticles: Applications and hazards. Int. J. Nanomedicine 2008, 3, 133–149.

    Article  Google Scholar 

  40. Ruan, C. H.; Zhang, L. F.; Qin, Y. L.; Xu, C.; Zhang, X. B.; Wan, J. M.; Peng, Z. G.; Shi, J. J.; Li, X. Y.; Wang, L. Synthesis of porphyrin sensitized TiO2/graphene and its photocatalytic property under visible light. Mater. Lett. 2015, 141, 362–365.

    Article  Google Scholar 

  41. Rahimi, R.; Zargari, S.; Yousefi, A.; Berijani, M. Y.; Ghaffarinejad, A.; Morsali, A. Visible light photocatalytic disinfection of E. coli with TiO2–graphene nanocomposite sensitized with tetrakis (4-carboxyphenyl) porphyrin. Appl. Surf. Sci. 2015, 355, 1098–1106.

    Article  Google Scholar 

  42. Zargari, S.; Rahimi, R.; Yousefi, A. An efficient visible light photocatalyst based on tin porphyrin intercalated between TiO2–graphene nanosheets for inactivation of E. coli and investigation of charge transfer mechanism. RSC Adv. 2016, 6, 24218–24228.

    Article  Google Scholar 

  43. Bhaumik, J.; Mittal, A. K.; Banerjee, A.; Chisti, Y.; Banerjee, U. C. Applications of phototheranostic nanoagents in photodynamic therapy. Nano Res. 2015, 8, 1373–1394.

    Article  Google Scholar 

  44. Ikari, K.; Momohara, S. Bone changes in rheumatoid arthritis. N. Engl. J. Med. 2005, 353, e13.

    Article  Google Scholar 

  45. Marmont, A. M.; Van Lint, M. T.; Gualandi, F.; Bacigalupo, A. Autologous marrow stem cell transplantation for severe systemic lupus erythematosus of long duration. LUPUS 1997, 6, 545–548.

    Article  Google Scholar 

  46. Augello, A.; Tasso, R.; Negrini, S. M.; Cancedda, R.; Pennesi, G. Cell therapy using allogeneic bone marrow mesenchymal stem cells prevents tissue damage in collageninduced arthritis. Arthritis Rheum. 2007, 56, 1175–1186.

    Article  Google Scholar 

  47. Ezashi, T.; Das, P.; Roberts, R. M. Low O2 tensions and the prevention of differentiation of hES cells. Proc. Natl. Acad. Sci. USA 2005, 102, 4783–4788.

    Article  Google Scholar 

  48. Danet, G. H.; Pan, Y.; Luongo, J. L.; Bonnet, D. A.; Simon, M. C. Expansion of human SCID-repopulating cells under hypoxic conditions. J. Clin. Invest. 2003, 112, 126–135.

    Article  Google Scholar 

  49. Morrison, S. J.; Csete, M.; Groves, A. K.; Melega, W.; Wold, B.; Anderson, D. J. Culture in reduced levels of oxygen promotes clonogenic sympathoadrenal differentiation by isolated neural crest stem cells. J. Neurosci. 2000, 20, 7370–7376.

    Google Scholar 

  50. McInnes, I. B.; Liew, F. Y. Cytokine networks—Towards new therapies for rheumatoid arthritis. Nat. Clin. Pract. Rheumatol. 2005, 1, 31–39.

    Article  Google Scholar 

  51. Wang, F. F.; Zhai, D.; Wu, C. T.; Chang, J. Multifunctional mesoporous bioactive glass/upconversion nanoparticle nanocomposites with strong red emission to monitor drug delivery and stimulate osteogenic differentiation of stem cells. Nano Res. 2016, 9, 1193–1208.

    Article  Google Scholar 

  52. Turner, L.-A.; Dalby, M. J. Nanotopography—Potential relevance in the stem cell niche. Biomater. Sci. 2014, 2, 1574–1594.

    Article  Google Scholar 

  53. Chang, B.; Song, W.; Han, T. X.; Yan, J.; Li, F. P.; Zhao, L. Z.; Kou, H. C.; Zhang, Y. M. Influence of pore size of porous titanium fabricated by vacuum diffusion bonding of titanium meshes on cell penetration and bone ingrowth. Acta Biomater. 2016, 33, 311–321.

    Article  Google Scholar 

  54. Brest, P.; Lapaquette, P.; Souidi, M.; Lebrigand, K.; Cesaro, A.; Vouret-Craviari, V.; Mari, B.; Barbry, P.; Mosnier, J.-F.; Hébuterne, X. et al. A synonymous variant in IRGM alters a binding site for miR-196 and causes deregulation of IRGM-dependent xenophagy in Crohn's disease. Nat. Genet. 2011, 43, 242–245.

    Article  Google Scholar 

  55. Li, Y.; Xu, X. J.; Liang, Y.; Liu, S. Y.; Xiao, H. S.; Li, F.; Cheng, H.; Fu, Z. Z. miR-375 enhances palmitate-induced lipoapoptosis in insulin-secreting NIT-1 cells by repressing myotrophin (V1) protein expression. Int. J. Clin. Exp. Pathol. 2010, 3, 254–264.

    Google Scholar 

  56. Poy, M. N.; Eliasson, L.; Krutzfeldt, J.; Kuwajima, S.; Ma, X. S.; MacDonald, P. E.; Pfeffer, S.; Tuschl, T.; Rajewsky, N.; Rorsman, P. et al. A pancreatic islet-specific microRNA regulates insulin secretion. Nature 2004, 432, 226–230.

    Article  Google Scholar 

  57. Georgantas, R. W.; Hildreth, R.; Morisot, S.; Alder, J.; Liu, C.-G.; Heimfeld, S.; Calin, G. A.; Croce, C. M.; Civin, C. I. CD34+ hematopoietic stem-progenitor cell microRNA expression and function: A circuit diagram of differentiation control. Proc. Natl. Acad. Sci. USA 2007, 104, 2750–2755.

    Article  Google Scholar 

  58. Huang, X. A.; Lin, H. The microRNA regulation of stem cells. Wiley Interdiscip. Rev. Dev. Biol. 2012, 1, 83–95.

    Google Scholar 

  59. Garzon, R.; Croce, C. M. MicroRNAs in normal and malignant hematopoiesis. Curr. Opin. Hematol. 2008, 15, 352–358.

    Article  Google Scholar 

  60. Neilson, J. R.; Zheng, G. X. Y.; Burge, C. B.; Sharp, P. A. Dynamic regulation of miRNA expression in ordered stages of cellular development. Genes Dev. 2007, 21, 578–589.

    Article  Google Scholar 

  61. Selbach, M.; Schwanhäusser, B.; Thierfelder, N.; Fang, Z.; Khanin, R.; Rajewsky, N. Widespread changes in protein synthesis induced by microRNAs. Nature 2008, 455, 58–63.

    Article  Google Scholar 

  62. Costinean, S.; Zanesi, N.; Pekarsky, Y.; Tili, E.; Volinia, S.; Heerema, N.; Croce, C. M. Pre-B cell proliferation and lymphoblastic leukemia/high-grade lymphoma in Eμ-miR155 transgenic mice. Proc. Natl. Acad. Sci. USA 2006, 103, 7024–7029.

    Article  Google Scholar 

  63. Rodriguez, A.; Vigorito, E.; Clare, S.; Warren, M. V.; Couttet, P.; Soond, D. R.; van Dongen, S.; Grocock, R. J.; Das, P. P.; Miska, E. A. Requirement of bic/microRNA-155 for normal immune function. Science 2007, 316, 608–611.

    Article  Google Scholar 

  64. Blüml, S.; Bonelli, M.; Niederreiter, B.; Puchner, A.; Mayr, G.; Hayer, S.; Koenders, M. I.; van den Berg, W. B.; Smolen, J.; Redlich, K. Essential role of microRNA-155 in the pathogenesis of autoimmune arthritis in mice. Arthritis Rheum. 2011, 63, 1281–1288.

    Article  Google Scholar 

  65. Zhou, S. Y.; Wang, Y.; Meng, Y.; Xiao, C. Y.; Liu, Z.; Brohawn, P.; Higgs, B. W.; Jallal, B.; Jia, Q.; Qu, B. et al. In vivo therapeutic success of microRNA-155 antagomir in a mouse model of lupus alveolar hemorrhage. Arthritis Rheumatol. 2016, 68, 953–964.

    Article  Google Scholar 

  66. Mizuno, Y.; Yagi, K.; Tokuzawa, Y.; Kanesaki-Yatsuka, Y.; Suda, T.; Katagiri, T.; Fukuda, T.; Maruyama, M.; Okuda, A.; Amemiya, T. et al. miR-125b inhibits osteoblastic differentiation by down-regulation of cell proliferation. Biochem. Biophys. Res. Commun. 2008, 368, 267–272.

    Article  Google Scholar 

  67. Itoh, T.; Nozawa, Y.; Akao, Y. MicroRNA-141 and -200a are involved in bone morphogenetic protein-2-induced mouse pre-osteoblast differentiation by targeting distal-less homeobox 5. J. Biol. Chem. 2009, 284, 19272–19279.

    Article  Google Scholar 

  68. Anderson, C.; Catoe, H.; Werner, R. MIR-206 regulates connexin43 expression during skeletal muscle development. Nucleic Acids Res. 2006, 34, 5863–5871.

    Article  Google Scholar 

  69. Caretti, G.; Di Padova, M.; Micales, B.; Lyons, G. E.; Sartorelli, V. The Polycomb Ezh2 methyltransferase regulates muscle gene expression and skeletal muscle differentiation. Genes Dev. 2004, 18, 2627–2638.

    Article  Google Scholar 

  70. Li, Y.-T.; Chen, S.-Y.; Wang, C.-R.; Liu, M.-F.; Lin, C.-C.; Jou, I. M.; Shiau, A.-L.; Wu, C.-L. Brief Report: Amelioration of collagen-induced arthritis in mice by lentivirus-mediated silencing of microRNA-223. Arthritis Rheum. 2012, 64, 3240–3245.

    Article  Google Scholar 

  71. Parasuraman, S.; Raveendran, R.; Kesavan, R. Blood sample collection in small laboratory animals. J. Pharmacol. Pharmacother. 2010, 1, 87–93.

    Article  Google Scholar 

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Synergy and translation of allogenic bone marrow stem cells after photodynamic treatment of rheumatoid arthritis with tetra sulfonatophenyl porphyrin and TiO2 nanowhiskers

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Rehman, F.U., Zhao, C., Wu, C. et al. Synergy and translation of allogenic bone marrow stem cells after photodynamic treatment of rheumatoid arthritis with tetra sulfonatophenyl porphyrin and TiO2 nanowhiskers. Nano Res. 9, 3305–3321 (2016). https://doi.org/10.1007/s12274-016-1208-5

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