OBJECTIVE: Cyclosporine A (CsA), known as an effective immunosuppressive agent, is widely used in clinical fields. Mesenchymal stem cells may exert immunomodulatory effects on the immune system, but the exact mechanisms underlying them remain controversial. Here we investigated whether human adipose tissue-derived mesenchymal stem cells (AMSCs) facilitate in vitro the immunomodulatory effects of CsA and we explored the molecule mechanisms that may be involved. MATERIALS AND METHODS: Proliferation of T lymphocytes was measured by uptake of (3)H-thymidine. Transcription and production of interleukin-2 and interferon-γ were evaluated by real-time quantitative polymerase chain reaction, reverse transcription polymerase chain reaction, and enzyme-linked immunosorbent assay. Nuclear factor-κB (NF-κB) was assayed by Western blotting and electrophoretic mobility shift assay. Expression of Jagged-1, Jagged-2, and Delta-1 of AMSCs were surveyed by flow cytometric analysis and Western blotting. RESULTS: The combination of moderate-dose AMSCs and low-dose CsA was significantly more powerful than moderate-dose AMSCs or large-dose CsA alone in suppressing transcription and production of interleukin-2 and interferon-γ, activation of NF-κB, and proliferation of T lymphocytes. In addition, AMSCs expressed a high level of Jagged-1, which induced activation of Notch signaling in T lymphocytes, thus reducing NF-κB activity. Anti-Jagged-1 neutralizing antibody and N [N-(3, 5-difluorophenacetyl-L-alanyl)]-S-phenylglycine t-butyl ester could reverse this trend. CONCLUSIONS: Human AMSCs facilitate the immunosuppressive effect of CsA on T lymphocytes through Jagged-1/Notch-related inhibition of NF-κB signaling. The combination of AMSCs and CsA represents a rationale therapeutic approach aimed to prevent adverse effects of CsA while maintaining its adequate immunosuppressive effect. Expression of Jagged-1 on AMSCs may provide an effective mechanism for the immunomodulatory activity of AMSCs via direct cell-cell interaction.
OBJECTIVE: Cyclosporine A (CsA), known as an effective immunosuppressive agent, is widely used in clinical fields. Mesenchymal stem cells may exert immunomodulatory effects on the immune system, but the exact mechanisms underlying them remain controversial. Here we investigated whether human adipose tissue-derived mesenchymal stem cells (AMSCs) facilitate in vitro the immunomodulatory effects of CsA and we explored the molecule mechanisms that may be involved. MATERIALS AND METHODS: Proliferation of T lymphocytes was measured by uptake of (3)H-thymidine. Transcription and production of interleukin-2 and interferon-γ were evaluated by real-time quantitative polymerase chain reaction, reverse transcription polymerase chain reaction, and enzyme-linked immunosorbent assay. Nuclear factor-κB (NF-κB) was assayed by Western blotting and electrophoretic mobility shift assay. Expression of Jagged-1, Jagged-2, and Delta-1 of AMSCs were surveyed by flow cytometric analysis and Western blotting. RESULTS: The combination of moderate-dose AMSCs and low-dose CsA was significantly more powerful than moderate-dose AMSCs or large-dose CsA alone in suppressing transcription and production of interleukin-2 and interferon-γ, activation of NF-κB, and proliferation of T lymphocytes. In addition, AMSCs expressed a high level of Jagged-1, which induced activation of Notch signaling in T lymphocytes, thus reducing NF-κB activity. Anti-Jagged-1 neutralizing antibody and N [N-(3, 5-difluorophenacetyl-L-alanyl)]-S-phenylglycine t-butyl ester could reverse this trend. CONCLUSIONS:Human AMSCs facilitate the immunosuppressive effect of CsA on T lymphocytes through Jagged-1/Notch-related inhibition of NF-κB signaling. The combination of AMSCs and CsA represents a rationale therapeutic approach aimed to prevent adverse effects of CsA while maintaining its adequate immunosuppressive effect. Expression of Jagged-1 on AMSCs may provide an effective mechanism for the immunomodulatory activity of AMSCs via direct cell-cell interaction.
Authors: Jeffrey M Gimble; Bruce A Bunnell; Trivia Frazier; Brian Rowan; Forum Shah; Caasy Thomas-Porch; Xiying Wu Journal: Organogenesis Date: 2013-01-01 Impact factor: 2.500
Authors: Vasileios Karantalis; Viky Y Suncion-Loescher; Luiza Bagno; Samuel Golpanian; Ariel Wolf; Cristina Sanina; Courtney Premer; Anthony J Kanelidis; Frederic McCall; Bo Wang; Wayne Balkan; Jose Rodriguez; Marcos Rosado; Azorides Morales; Konstantinos Hatzistergos; Makoto Natsumeda; Irene Margitich; Ivonne Hernandez Schulman; Samirah A Gomes; Muzammil Mushtaq; Darcy L DiFede; Joel E Fishman; Pradip Pattany; Juan Pablo Zambrano; Alan W Heldman; Joshua M Hare Journal: J Am Coll Cardiol Date: 2015-11-03 Impact factor: 24.094