title: Designing 3D Mesenchymal Stem Cell Sheets Merging Magnetic and Fluorescent Features: When Cell Sheet Technology Meets Image-Guided Cell Therapy.
abstract: Cell sheet technology opens new perspectives in tissue regeneration therapy by providing readily implantable, scaffold-free 3D tissue constructs. Many studies have focused on the therapeutic effects of cell sheet implantation while relatively little attention has concerned the fate of the implanted cells in vivo. The aim of the present study was to track longitudinally the cells implanted in the cell sheets in vivo in target tissues. To this end we (i) endowed bone marrow-derived mesenchymal stem cells (BMMSCs) with imaging properties by double labeling with fluorescent and magnetic tracers, (ii) applied BMMSC cell sheets to a digestive fistula model in mice, (iii) tracked the BMMSC fate in vivo by MRI and probe-based confocal laser endomicroscopy (pCLE), and (iv) quantified healing of the fistula. We show that image-guided longitudinal follow-up can document both the fate of the cell sheet-derived BMMSCs and their healing capacity. Moreover, our theranostic approach informs on the mechanism of action, either directly by integration of cell sheet-derived BMMSCs into the host tissue or indirectly through the release of signaling molecules in the host tissue. Multimodal imaging and clinical evaluation converged to attest that cell sheet grafting resulted in minimal clinical inflammation, improved fistula healing, reduced tissue fibrosis and enhanced microvasculature density. At the molecular level, cell sheet transplantation induced an increase in the expression of anti-inflammatory cytokines (TGF-ß2 and IL-10) and host intestinal growth factors involved in tissue repair (EGF and VEGF). Multimodal imaging is useful for tracking cell sheets and for noninvasive follow-up of their regenerative properties.
authors.affiliation: 1. Laboratoire Imagerie de l'Angiogénèse, Plateforme d'Imagerie du Petit Animal, INSERM U970, Université Paris Descartes, 56 Rue Leblanc, 75015 Paris, France.; 2. Gastroenterology and Endoscopy Department, Hôpital Européen Georges Pompidou, APHP, Université Paris Descartes, 20 rue Leblanc, 75015 Paris, France.
authors.forename: Gabriel
authors.initials: G
authors.lastname: Rahmi
authors.affiliation: 1. Laboratoire Imagerie de l'Angiogénèse, Plateforme d'Imagerie du Petit Animal, INSERM U970, Université Paris Descartes, 56 Rue Leblanc, 75015 Paris, France.
authors.forename: Laetitia
authors.initials: L
authors.lastname: Pidial
authors.affiliation: 3. Laboratoire Matières et Systèmes Complexes (MSC), UMR 7057 CNRS, Université Paris-Diderot, 10 rue Alice Domon et Léonie Duquet, 75205 Paris cedex 13, France.
authors.forename: Amanda K A
authors.initials: AK
authors.lastname: Silva
authors.affiliation: 1. Laboratoire Imagerie de l'Angiogénèse, Plateforme d'Imagerie du Petit Animal, INSERM U970, Université Paris Descartes, 56 Rue Leblanc, 75015 Paris, France.
authors.forename: Eléonore
authors.initials: E
authors.lastname: Blondiaux
authors.affiliation: 4. Laboratory of Intestinal Immunity, Institut IMAGINE-INSERM 1163, 24 boulevard du Montparnasse, 75015 Paris, France.
authors.forename: Bertrand
authors.initials: B
authors.lastname: Meresse
authors.affiliation: 3. Laboratoire Matières et Systèmes Complexes (MSC), UMR 7057 CNRS, Université Paris-Diderot, 10 rue Alice Domon et Léonie Duquet, 75205 Paris cedex 13, France.
authors.forename: Florence
authors.initials: F
authors.lastname: Gazeau
authors.affiliation: 1. Laboratoire Imagerie de l'Angiogénèse, Plateforme d'Imagerie du Petit Animal, INSERM U970, Université Paris Descartes, 56 Rue Leblanc, 75015 Paris, France.
authors.forename: Gwennhael
authors.initials: G
authors.lastname: Autret
authors.affiliation: 1. Laboratoire Imagerie de l'Angiogénèse, Plateforme d'Imagerie du Petit Animal, INSERM U970, Université Paris Descartes, 56 Rue Leblanc, 75015 Paris, France.
authors.forename: Daniel
authors.initials: D
authors.lastname: Balvay
authors.affiliation: 1. Laboratoire Imagerie de l'Angiogénèse, Plateforme d'Imagerie du Petit Animal, INSERM U970, Université Paris Descartes, 56 Rue Leblanc, 75015 Paris, France.; 5. Radiology Department, Hôpital Européen Georges Pompidou, APHP, Université Paris Descartes, 20 rue Leblanc, 75015 Paris, France.
authors.forename: Charles André
authors.initials: CA
authors.lastname: Cuenod
authors.affiliation: 6. Department of Digestive and Endocrine Surgery, Nouvel Hôpital Civil, and Institut de Recherche contre les Cancers de l'Appareil Digestif (IRCAD), 1 place de l'Hôpital, 67091 Strasbourg Cedex, France.
authors.forename: Silvana
authors.initials: S
authors.lastname: Perretta
authors.affiliation: 1. Laboratoire Imagerie de l'Angiogénèse, Plateforme d'Imagerie du Petit Animal, INSERM U970, Université Paris Descartes, 56 Rue Leblanc, 75015 Paris, France.
authors.forename: Bertrand
authors.initials: B
authors.lastname: Tavitian
authors.affiliation: 3. Laboratoire Matières et Systèmes Complexes (MSC), UMR 7057 CNRS, Université Paris-Diderot, 10 rue Alice Domon et Léonie Duquet, 75205 Paris cedex 13, France.
authors.forename: Claire
authors.initials: C
authors.lastname: Wilhelm
authors.affiliation: 2. Gastroenterology and Endoscopy Department, Hôpital Européen Georges Pompidou, APHP, Université Paris Descartes, 20 rue Leblanc, 75015 Paris, France.
authors.forename: Christophe
authors.initials: C
authors.lastname: Cellier
authors.affiliation: 1. Laboratoire Imagerie de l'Angiogénèse, Plateforme d'Imagerie du Petit Animal, INSERM U970, Université Paris Descartes, 56 Rue Leblanc, 75015 Paris, France.; 5. Radiology Department, Hôpital Européen Georges Pompidou, APHP, Université Paris Descartes, 20 rue Leblanc, 75015 Paris, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Clément
mesh_terms: D000818:Animals; D002470:Cell Survival; D064987:Cell- and Tissue-Based Therapy / Q000379:methods*; D004066:Digestive System Diseases / Q000628:therapy; D004195:Disease Models, Animal; D005402:Fistula / Q000628:therapy; D048091:Guided Tissue Regeneration / Q000379:methods*; D008137:Longitudinal Studies; D008279:Magnetic Resonance Imaging; D059630:Mesenchymal Stem Cells / Q000502:physiology*; D051379:Mice; D018613:Microscopy, Confocal; D013194:Staining and Labeling; D016896:Treatment Outcome
keywords: MRI; cell sheet technology; fluorescence imaging; image-guided cell therapy; intestinal fistula.