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Exosomes from Mesenchymal Stem Cells are Anti-Inflammatory Mediators in VCA
Jonathan P. Massie, BS, Catherine C. Motosko, BS, Trevor J. Ellison, BS, Sophia G. Hameedi, BA, Bukhtawar Waqas, BA, J. Rodrigo Diaz-Siso, MD, Daniel J. Ceradini, MD.
NYU Langone Medical Center, New York, NY, USA.

PURPOSE:
Mesenchymal stem cells(MSCs) are immunomodulators investigated in vascularized composite allotransplantation(VCA), yet their mechanism is poorly defined. We hypothesized that MSCs package anti-inflammatory cytokines into exosomes(EXO) which execute the immunomodulatory effects of MSCs, and differential EXO packaging could be driven by oxygen tension and inflammatory milieu. Our aims were:(1)Determine whether MSCs secrete EXOs;(2)Characterize MSC-EXO cargo under differential conditions;(3)Investigate MSC-EXOs in preventing rejection in VCA.
METHODS:
Lewis rat-derived MSCs were cultured in normoxia(21% O2), hypoxia(5% O2), or with 100U IFNγ. MSC-EXOs were isolated by ultracentrifugation and confirmed by TEM, immunoblot, and flow cytometry for EXO markers. MSC-EXO cytokine cargo were characterized by flow cytometry, and assessed for syngeneic Treg induction, and in an allogeneic rat hindlimb VCA model.
RESULTS:
MSC-EXOs from normoxic, hypoxic, and IFNγ-primed MSCs expressed EXO markers Cd63 and Cd81. Hypoxic MSC-EXOs packaged significantly greater quantities of IDO(6.4-fold,p<0.0001), IL-10(1.4-fold,p<0.05), iNOS(2.1-fold,p<0.0001), PGE2(1.7-fold,p<0.05) and TGFβ(1.4-fold,p<0.005) versus an isotype control. IFNγ-primed MSCs packaged greater quantities of iNOS and TGFβ compared to normoxic and hypoxic MSC-EXOs(p<0.05 for all). Normoxic MSC-EXOs induced a 6-fold increase in a CD4+FoxP3+ Treg population(p<0.005) versus negative control; a 2-fold greater induction than normoxic MSCs(p<0.0001).In a VCA model, ex vivo seeded DiI-labeled MSC-EXOs localized to the perivascular space following re-implantation.
CONCLUSION:
MSC-EXOs package all known mediators of MSC immunomodulation and stimulate Treg production. Preliminary VCA studies suggest that MSC-EXOs localize to sites of immunologic importance similar to MSCs. MSC-EXOs are a promising explanation for MSC immunomodulatory properties, and may offer a novel therapeutic approach in VCA.


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