Abstract
BackgroundThe long-term survival after vascularized composite allotransplantation (VCA) is often limited by systemic rejection as well as the adverse effects of immunosuppressants. The stromal vascular fraction (SVF) can be expanded to produce adipose-derived stem cells (ADSC) which represents a combination of endothelial cells, preadipocytes, immune cells, and ADSC. It has been demonstrated that ADSC possess consistently reliable clinical results. However, literature is scarce regarding SVF in VCA. This study seeks to determine the impact of ex vivo allograft pretreatment in combination with SVF cells in the ability to promote composite tissue allotransplantation immunotolerance.MethodsA rat hind limb allotransplant model was used to investigate the influence of ex vivo pretreatment of SVF and ADSC on VCA survival. Intravascular cell-free saline, ADSC, or SVF was infused into the models with immunosuppressants. The histopathological examination and duration that the allografts went without displaying symptoms of rejection was documented. Peripheral T lymphocytes and Tregs were quantified with flow cytometry while allotissue expressions of CD31 were quantified with immunohistochemical staining (IHC). ELISA was used to detect vascular endothelial growth factor (VEGF)-A as well as anti- and pro-inflammatory cytokines.ResultsWe demonstrated that ex vivo treatment of allografts with SVF or ADSC prolonged allograft survival in contrast to medium control cohorts. There were also enhanced levels of immunomodulatory cytokines and increased VEGF-A and CD31 expression as well as reduced infiltration and proliferation of T lymphocytes along with raised Treg expressions.ConclusionThese studies demonstrated that adipose-derived cellular therapies prolong graft survival in an allogenic hind limb transplantation model and have the potential to establish immunotolerance.
Highlights
The long-term survival after vascularized composite allotransplantation (VCA) is often limited by systemic rejection as well as the adverse effects of immunosuppressants
A previous study in a rat model hind limb transplantation demonstrated that infused bone marrow-derived stromal cells (BMSC) into the allografts prolonged survival of transplanted hind limbs [15]
Our group previously demonstrated the importance of adipose-derived stem cells (ADSC) pre-treatment as an adjunct for improving allograft survival in VCA [18]
Summary
The long-term survival after vascularized composite allotransplantation (VCA) is often limited by systemic rejection as well as the adverse effects of immunosuppressants. It has the ability to restore function and appearance of damaged tissues in these patients [1, 2] The ability of this modality of treatment is limited by the requirement of multiple immunosuppressant medications to allow for the grafts to survive in the recipient’s body [3, 4]. It is essential for newer therapies that are able to effectively suppress the alloreactive immune response, opening up this treatment method to a larger population. A previous study in a rat model hind limb transplantation demonstrated that infused BMSC into the allografts prolonged survival of transplanted hind limbs [15]
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