Heparan Sulfate Mimetics: A New Way to Optimize Therapeutic Effects of Hydrogel-Embedded Mesenchymal Stromal Cells in Colonic Radiation-Induced Damage

Lara Moussa,Pierre Weiss,Jérôme Guicheux,Gildas Réthoré,Denis Barritault,Girish Pattapa,Christelle Demarquay,Fernando Siñeriz,Noëlle Mathieu,Mohamed Amine Benadjaoud

doi:10.1038/s41598-018-36631-6

Abstract

Clinical expression of gastrointestinal radiation toxicity on non-cancerous tissue could be very life threatening and clinicians must deal increasingly with the management of late side effects of radiotherapy. Cell therapy, in particular mesenchymal stromal cell (MSC) therapy, has shown promising results in numerous preclinical animal studies and thus has emerged as a new hope for patient refractory to current treatments. However, many stem cell clinical trials do not confer any beneficial effect suggesting a real need to accelerate research towards the successful clinical application of stem cell therapy. In this study, we propose a new concept to improve the procedure of MSC-based treatment for greater efficacy and clinical translatability. We demonstrated that heparan sulfate mimetic (HS-m) 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 increase cell engraftment and cell survival, improve the therapeutic benefit of MSC treatment in two animal models relevant of the human pathology. For the first time, a decrease of the injury score in the ulcerated area was observed with this combined treatment. We also demonstrated that the combined treatment favored the epithelial regenerative process. 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 radiotherapy.

Highlights

Intestinal radiation toxicity is a complex process involving inflammation, epithelial stem-cell death, and activation of endothelial cells and immune system associated with persistent oxidative stress
We demonstrated that irradiated rats treated with heparan sulfate mimetic (HS-m) exhibit slight decrease of the injury score in the regenerative and dystrophic areas compared with irradiated rats (Fig. 2B)
In our lab, we previously demonstrated that a local injection of mesenchymal stromal cell (MSC) within a Si-HPMC hydrogel increased MSC engraftment associated with the improvement of the colonic function and structure in the margin zones after irradiation

Summary

Introduction

Intestinal radiation toxicity is a complex process involving inflammation, epithelial stem-cell death, and activation of endothelial cells and immune system associated with persistent oxidative stress. The major surgical problem is the dehiscence of tissues causing a leakage of the anastomosis This wound healing failure could be due to excessive inflammation and impaired ECM induced after irradiation. Various studies suggested that the beneficial effects of MSCs were related to their secretion of bioactive molecules[12,13] In this sense, we recently demonstrated that a local injection of MSCs within a hydrogel (Silanized HydroxyPropylMethyl Cellulose Si-HPMC) through colonoscopy allows a decrease of the number of injected cells, increases the rate of MSC engraftment in the area requiring repair and improves the function of epithelial barrier in the colon[14].

Objectives

Methods

Results

Discussion

Conclusion