title: Nanofibrous clinical-grade collagen scaffolds seeded with human cardiomyocytes induces cardiac remodeling in dilated cardiomyopathy.
abstract: Limited data are available on the effects of stem cells in non-ischemic dilated cardiomyopathy (DCM). Since the diffuse nature of the disease calls for a broad distribution of cells, this study investigated the scaffold-based delivery of human induced pluripotent stem cell-derived cardiomyocytes (hiPS-CM) in a mouse model of DCM. Nanofibrous scaffolds were produced using a clinical grade atelocollagen which was electrospun and cross-linked under different conditions. As assessed by scanning electron microscopy and shearwave elastography, the optimum crosslinking conditions for hiPS-CM colonization proved to be a 10% concentration of citric acid crosslinking agent and 150 min of post-electrospinning baking. Acellular collagen scaffolds were first implanted in both healthy mice and those with induced DCM by a cardiac-specific invalidation of serum response factor (SRF). Seven and fourteen days after implantation, the safety of the scaffold was demonstrated by echocardiography and histological assessments. The subsequent step of implantation of the scaffolds seeded with hiPS-CM in DCM induced mice, using cell-free scaffolds as controls, revealed that after fourteen days heart function decreased in controls while it remained stable in the treated mice. This pattern was associated with an increased number of endothelial cells, in line with the greater vascularity of the scaffold. Moreover, a lesser degree of fibrosis consistent with the upregulation of several genes involved in extracellular matrix remodeling was observed. These results support the interest of the proposed hiPS-CM seeded electrospun scaffold for the stabilization of the DCM outcome with potential for its clinical use in the future.
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, Institut de Biologie Paris-Seine (IBPS), UMR CNRS 8256, Biological Adaptation and Ageing, 75005, Paris, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Joanne
authors.affiliation: Ecole Normale Supérieure-PSL Research University, Sorbonne Universités, UPMC Univ Paris 06, UMR CNRS 8640, PASTEUR, 75005, Paris, France.
authors.forename: Maria
authors.initials: M
authors.lastname: Kitsara
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, Institut de Biologie Paris-Seine (IBPS), UMR CNRS 8256, Biological Adaptation and Ageing, 75005, Paris, France.
authors.forename: Solène-Emmanuelle
authors.initials: SE
authors.lastname: Boitard
authors.affiliation: Université Sorbonne Paris Cité, Univ Paris Descartes, INSERM U970, 75015, Paris, France; Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Department of Cardiology, 75015, Paris, France.
authors.forename: Hany
authors.initials: H
authors.lastname: Naemetalla
authors.affiliation: Assistance Publique-Hôpitaux de Paris, Hôpital Saint-Louis, Unité de Thérapie Cellulaire, 75010, Paris, France; INSERM UMR 1160, Centre d'Investigation Clinique en Biothérapies (CIC1427), 75010, Paris, France.
authors.forename: Valérie
authors.initials: V
authors.lastname: Vanneaux
authors.affiliation: Institut Langevin, ESPCI ParisTech, PSL Research University, UMR 7587 CNRS, U979 INSERM, Paris, France.
authors.forename: Mathieu
authors.initials: M
authors.lastname: Pernot
authors.affiliation: Assistance Publique-Hôpitaux de Paris, Hôpital Saint-Louis, Unité de Thérapie Cellulaire, 75010, Paris, France; INSERM UMR 1160, Centre d'Investigation Clinique en Biothérapies (CIC1427), 75010, Paris, France; Université Sorbonne Paris Cité, Paris, France.
authors.forename: Jérôme
authors.initials: J
authors.lastname: Larghero
authors.affiliation: Biom'Up, 69800, Saint-Priest, France.
authors.forename: Patricia
authors.initials: P
authors.lastname: Forest
authors.affiliation: Ecole Normale Supérieure-PSL Research University, Sorbonne Universités, UPMC Univ Paris 06, UMR CNRS 8640, PASTEUR, 75005, Paris, France.
authors.forename: Yong
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Université Sorbonne Paris Cité, Univ Paris Descartes, INSERM U970, 75015, Paris, France; Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Department of Cardiovascular Surgery, 75015, Paris, France; Université Sorbonne Paris Cité, Paris, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Menasché
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, Institut de Biologie Paris-Seine (IBPS), UMR CNRS 8256, Biological Adaptation and Ageing, 75005, Paris, France. Electronic address: onnik.agbulut@upmc.fr.
authors.forename: Onnik
authors.initials: O
authors.lastname: Agbulut
mesh_terms: D000818:Animals; D002311:Cardiomyopathy, Dilated / Q000503:physiopathology / Q000628:therapy*; D002460:Cell Line; D003094:Collagen / Q000737:chemistry*; D006321:Heart / Q000502:physiology / Q000503:physiopathology; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000166:cytology*; D008810:Mice, Inbred C57BL; D032383:Myocytes, Cardiac / Q000166:cytology / Q000637:transplantation*; D057139:Nanofibers / Q000737:chemistry*; D054457:Tissue Scaffolds / Q000737:chemistry*
chemical_list: C059821:atelocollagen; D003094:Collagen
keywords: Cardiac cell therapy; Cardiomyopathy; Collagen scaffold; Electrospinning; Induced pluripotent stem cells