Abstract 12298: Inducible Nitric Oxide Synthase Expression in Mesenchymal Stromal Cells Induces Immunomodulation but Enhances Tumorigenic Conversion in Allogenic Cell Sheet Transplantation for Rat Myocardial Infarction
Background: Mesenchymal stromal cell (MSC) reportedly induce immune tolerance against allogenic antigens via inflammation-related expression of inducible nitric oxide synthase (iNOS). Combination of MSC may be promising therapeutic option in treating allogenic cell for cell therapy. However, tumorigenic conversion of MSCs is a major concern. Here, we hypothesized that immunomodulation property induced by iNOS in MSC impacts their tumorigenic conversion. We evaluated tumor formation following combined transplantation of iNOS-expressing MSCs with allogenic skeletal myoblasts in a rat model of myocardial infarction.
Methods and Results: Fischer rat-derived MSCs were prepared as a cell sheet for transplantation on the surface of the infarcted or normal myocardium of Wistar rats. Seven days after transplantation, iNOS expression of the cell sheet which was transplanted on the infarcted myocardium was greater than that transplanted on the normal myocardium. Next, iNOS expression in the MSC was enhanced by interferon-γ and lipopolysaccharide (IL) treatment before creating cell sheet. Survivals of luciferase-expressing L6 skeletal myoblasts following subcutaneous cell-sheet transplantation were evaluated by in vivo imaging. Addition of the MSCs to the L6 sheet prolonged the survival of the L6 cells, which was further extended by IL treatment of MSCs prior to the cell sheet preparation. Then, we transplanted cell sheets over the infarcted myocardium of Wistar rats. Tumor growth was not observed in the rats that received allogenic skeletal myoblast sheets at 28 days. While, mixed cell sheets transplanted over the infarcted myocardium showed formation of MSC-derived tumors (2 / 10), and tumor formation elevated by the IL pre-treatment in MSCs (8 / 10).
Conclusion: Inflammatory stimulation, such as transplantation to the infarcted myocardium or IL treatment in vitro enhanced iNOS expression in MSCs, prolonging the survival of transplanted allogenic myoblast cell sheets. However, iNOS expression in the MSCs was also associated with tumorigenic conversion, indicating that iNOS expression in MSCs should be considered when optimizing the concomitant transplantation therapy of MSCs and allogenic cells for treatment of heart failure.
Author Disclosures: Y. Imanishi: None. E. Kankuri: None. A. Siltanen: None. S. Miyagawa: None. S. Fukushima: None. Y. Sawa: None. A. Harjula: None.
- © 2014 by American Heart Association, Inc.