ORIGINAL ARTICLE
Ex vivo allotransplantation engineering: Delivery of mesenchymal stem cells prolongs rejection-free allograft survival

https://doi.org/10.1111/ajt.14668Get rights and content
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Current pharmacologic regimens in transplantation prevent allograft rejection through systemic recipient immunosuppression but are associated with severe morbidity and mortality. The ultimate goal of transplantation is the prevention of allograft rejection while maintaining recipient immunocompetence. We hypothesized that allografts could be engineered ex vivo (after allotransplant procurement but before transplantation) by using mesenchymal stem cell–based therapy to generate localized immunomodulation without affecting systemic recipient immunocompetence. To this end, we evaluated the therapeutic efficacy of bone marrow–derived mesenchymal stem cells in vitro and activated them toward an immunomodulatory fate by priming in inflammatory or hypoxic microenvironments. Using an established rat hindlimb model for allotransplantation, we were able to significantly prolong rejection-free allograft survival with a single perioperative ex vivo infusion of bone marrow–derived mesenchymal stem cells through the allograft vasculature, in the absence of long-term pharmacologic immunosuppression. Critically, transplanted rats rejected a second, nonengineered skin graft from the same donor species to the contralateral limb at a later date, demonstrating that recipient systemic immunocompetence remained intact. This study represents a novel approach in transplant immunology and highlights the significant therapeutic opportunity of the ex vivo period in transplant engineering.

KEYWORDS

animal models: murine
basic (laboratory) research/science
immunosuppression/immune modulation
organ transplantation in general
rejection
stem cells
tolerance: experimental
tolerance: mechanisms
translational research/science
vascularized composite and reconstructive transplantation

Abbreviations

BMSC
bone marrow–derived mesenchymal stem cell
EC
endothelial cell
IDO
indoleamine 2,3-dioxygenase
IFN
interferon
iNOS
inducible nitric oxide synthase
IRI
ischemia–reperfusion injury
MSC
mesenchymal stem cell
PFA
paraformaldehyde
SDF1α
stromal cell–derived factor 1α
TGF
transforming growth factor
TNF
tumor necrosis factor

Cited by (0)

Marc A. Soares and Jonathan P. Massie contributed equally to the manuscript and project.