Strategies to improve Adipose Mesenchymal Stromal Cell Therapeutic Effect: Application to pelvic radiotherapy side effects

Abstract

Background & Aim Healthy tissues surrounding pelvic tumours may be impaired during radiotherapy (RT) and could lead to chronic gastrointestinal complications with substantial mortality. Injection of Adipose-derived Mesenchymal Stromal Cells (Ad-MSC) represents a promising therapeutic strategy. However, many stem cell clinical trials do not confer expected beneficial effect, suggesting a real need to accelerate research towards the successful clinical application. We hypothesized that heparan sulfate (HS)-mimetic injections that restore the extracellular matrix network and enhance the biological activity of growth factors, associated with local injection of MSC protected in a hydrogel that improves cell engraftment and cell survival, could improve the therapeutic benefit of MSC treatment. Methods, Results & Conclusion We used an experimental model of radiation proctitis developed in rats that reproduces severe colonic mucosal damages and fibrosis similar to those observed in patients treated by radiotherapy. We tested injections of HS-m, local injection through endoscopy of Ad-MSC embedded in Si-HPMC hydrogel as well as combinations of these various treatments. The therapeutic benefit was evaluated by endoscopy, histology and functional parameters as epithelial barrier were also tested. We demonstrated that hydrogel loaded-Ad-MSCs were viable, able to secrete trophic factors and responsive to the inflammatory environment. In animal model, Ad-MSC+Si-HPMC improve colonic epithelial structure and hyperpermeability. This therapeutic benefit is associated with greater engraftment of Si-HPMC-embedded Ad-MSCs in the irradiated colonic mucosa. We demonstrated that combination of HS-m to hydrogel-embedded MSC treatment enhances the therapeutic benefit of MSC therapy alone. We also demonstrated that the combined treatment favored the epithelial regenerative process. Finally, using an animal model of colonic surgery after irradiation, we demonstrated that the combined treatment improved rat survival, healing of the anastomosis and scar quality assessed by collagen deposit. In this study, we identified a new way, clinically applicable, to optimize stem-cell therapy and could be proposed to patients suffering from severe colonic defect after RT.