Abstract
BackgroundWe determined whether bone marrow mesenchymal stem cells (BMMSCs) transduced with heme oxygenase-1 (HO-1), a cytoprotective and immune-protective factor, could improve outcomes for small bowel transplantation (SBTx) in rats.MethodsWe performed heterotopic SBTx from Brown Norway rats to Lewis rats, before infusing Ad/HO-1-transduced BMMSCs (Ad/HO-1/BMMSCs) through the superficial dorsal veins of the penis. Respective infusions with Ad/BMMSCs, BMMSCs, and normal saline served as controls. The animals were sacrificed after 1, 5, 7, or 10 days. At each time point, we measured small bowel histology and apoptosis, HO-1 protein and mRNA expression, natural killer (NK) cell activity, cytokine concentrations in serum and intestinal graft, and levels of regulatory T (Treg) cells.ResultsThe saline-treated control group showed aggravated acute cellular rejection over time, with mucosal destruction, increased apoptosis, NK cell activation, and upregulation of proinflammatory and immune-related mediators. Both the Ad/BMMSC-treated group and the BMMSC-treated group exhibited attenuated acute cellular rejection at an early stage, but the effects receded 7 days after transplantation. Strikingly, the Ad/HO-1/BMMSC-treated group demonstrated significantly attenuated acute cellular rejection, reduced apoptosis and NK cell activity, and suppressed concentrations of inflammation and immune-related cytokines, and upregulated expression of anti-inflammatory cytokine mediators and increased Treg cell levels.ConclusionOur data suggest that Ad/HO-1-transduced BMMSCs have a reinforced effect on reducing acute rejection and protecting the outcome of SBTx in rats.
Highlights
We determined whether bone marrow mesenchymal stem cells (BMMSCs) transduced with heme oxygenase-1 (HO-1), a cytoprotective and immune-protective factor, could improve outcomes for small bowel transplantation (SBTx) in rats
BMMSCs transduced with recombinant adenovirus did not change in terms of cellular morphology (Fig. 1a) and were confirmed as BMMSCs based on their abilities for osteogenic differentiation and adipogenic differentiation in vitro (Fig. 1b, c)
The results demonstrated that transduction with recombinant adenovirus did not affect the molecular biological characteristics of BMMSCs
Summary
We determined whether bone marrow mesenchymal stem cells (BMMSCs) transduced with heme oxygenase-1 (HO-1), a cytoprotective and immune-protective factor, could improve outcomes for small bowel transplantation (SBTx) in rats. Small bowel transplantation (SBTx) is the sole therapeutic option for patients with irreversible intestinal failure. Due to the difficulties associated with the allogeneic immune response, long-term curative effects of SBTx are not comparable with other organ transplantations. Graft rejection rates for isolated intestinal transplants have decreased from 80% to 30–40% at experienced transplant centers, rejection remains the leading cause of graft failure or loss, and subsequently the main obstacle for further development of SBTx [1,2,3]. The therapeutic effects of MSCs in transplantation are largely restricted by the limited survival rate in vivo [20]. Outcomes have the potential to be improved if MSCs are accompanied with specific genetically engineered vectors designed to improve the MSC survival rate
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