Donor Adipose-derived Stromal Cells are Vasoprotectant but Unable to Revert Acute Rejection in Rodent Vascularized Composite Allotransplants

Riccardo Schweizer ^1,2,3* Pranitha Kamat ¹ Holger J Klein ^1,4 Branislav Kollar ^1,5 Matthias Waldner ¹ Klara Stoelzl ^1,6 Fabienne Lehner ^1,7 Souzan Salemi ⁸ Peter Bode ⁹ Daniel Eberli ⁸ Adriano Taddeo ¹⁰ Jan A. Plock ^1,3,4

• ¹ Plastic Surgery and Hand Surgery, University Hospital Zürich, Zurich, Zurich, Switzerland
• ² Lucerne Cantonal Hospital, University of Lucerne, Lucerne, Switzerland
• ³ University of Zurich, Zürich, Zürich, Switzerland
• ⁴ Plastic Surgery and Handsurgery, Aarau Cantonal Hospital, Aarau, Switzerland
• ⁵ Department of Plastic and Hand Surgery, Freiburg University Medical Center, Freiburg, Germany
• ⁶ University Hospital rechts der Isar, Technical University of Munich, Munich, Bavaria, Germany
• ⁷ Cantonal Hospital of Graubünden, Chur, Switzerland
• ⁸ Urology, University Hospital Zürich, Zurich, Zurich, Switzerland
• ⁹ Pathology, Cantonal Hospital Winterthur, Winterthur, Zürich, Switzerland
• ¹⁰ Department of Plastic and Hand Surgery, Inselspital University Hospital Bern, Bern, Bern, Switzerland

Background: Vascularized composite allotransplantation is successful in reconstruction of major defects of the upper extremity and face. Both rejection and vascular damage seriously endanger the outcome. The role of adipose-derived stromal cells (ASCs) in suppressing acute rejection of composite allotransplants and their short term protective effects on vessels remains widely unexplored. Methods: Systemic and local donor-derived ASCs (CD45-CD29+CD90+) versus FK-506 administration was evaluated for reversal of acute rejection and vascular alterations in fully mismatched rat hind-limb transplants. Results: ASC administration upon grade II rejection significantly delayed, but didn’t suppress progression to grade III rejection (7.6±1.0 days systemic, 7.1±1.1 days local vs. no cell therapy 2.9±1 days; p<0.01, n=38 animals). Pro-inflammatory cytokine blood levels significantly increased in controls from grade II to grade III rejection, while ASC significantly lowered levels for G-CSF, MIP-1α, MIP-3α, IL-1α, IL-1β, IL-18, and Rantes (p<0.05). Local and systemic PKH-26-labelled ASCs homed to the allograft and reversed intragraft vascular alterations in arterioles of rejecting skin and muscle, similarly to FK-506 treated controls (p<0.01). Conclusions: Although systemic and local ASC therapy reduces progression of acute rejection in vascularized composite allotransplantation, it is not able to revert rejection without additional immunosuppressive therapy. However, graft vasculitis during acute rejection is significantly reduced after cytotherapy.