Targeted Migration of Human Adipose-Derived Stem Cells to Secondary Lymphoid Organs Enhances Their Immunomodulatory Effect and Prolongs the Survival of Allografted Vascularized Composites

Abstract

The targeted delivery of therapeutic agents to secondary lymphoid organs (SLOs), which are the niches for immune initiation, provides an unprecedented opportunity for immune intolerance induction. The alloimmune rejection postvascularized composite allotransplantation (VCA) is mediated by T lymphocytes. Human adipose-derived stem cells (hASCs) possess the superiority of convenient availability and potent immunoregulatory property, but their therapeutic results in the VCA are unambiguous thus far. Chemokine receptor 7 (CCR7) can specifically guide immune cells migrating into SLOs. There, the genes of CCR7-GFP or GFP alone were introduced into hASCs by lentivirus. hASCs/CCR7 maintained the multidifferentiation and immunoregulatory abilities, but it gained the migration capacity elicited by secondary lymphoid organ chemokine (SCL) (CCR7 ligand) in vitro. Noteworthily, intravenously infused hASCs/CCR7 targetedly relocated in the T-cell aggression area in SLOs. In a rat VCA model, hASCs/GFP transfusion had a rare effect on the allografted vascularized composite. However, hASCs/CCR7 infusion potently prolonged the grafts' survival time. The ameliorated pathologic exhibition and the regulated inflammatory cytokines in the peripheral blood were also observed. The altered axis of Th1/Th2 and Tregs/Th17 in SLOs may underlie the downregulated rejection response. Moreover, the proteomic examination of splenic T lymphocytes also confirmed that hASCs/CCR7 decreased the proteins related to cytokinesis, lymphocyte proliferation, differentiation, and apoptotic process. In conclusion, our present study demonstrated that targeted migration of hASCs/CCR7 to SLOs highly intensifies their in vivo immunomodulatory effect in the VCA model for the first time. We believe this SLO-targeting strategy may improve the clinical therapeutic efficacy of hASC for allogeneic and autogenic immune disease. Stem Cells 2019;37:1581-1594.

Keywords: Adipose-derived stem cells; Chemokine receptor 7; Immunomodulatory effect; Secondary lymphoid organs; Vascularized composite allotransplantation.