title: Enhanced potency of cell-based therapy for ischemic tissue repair using an injectable bioactive epitope presenting nanofiber support matrix.
abstract: The translation of cell-based therapies for ischemic tissue repair remains limited by several factors, including poor cell survival and limited target site retention. Advances in nanotechnology enable the development of specifically designed delivery matrices to address these limitations and thereby improve the efficacy of cell-based therapies. Given the relevance of integrin signaling for cellular homeostasis, we developed an injectable, bioactive peptide-based nanofiber matrix that presents an integrin-binding epitope derived from fibronectin, and evaluated its feasibility as a supportive artificial matrix for bone marrow-derived pro-angiogenic cells (BMPACs) used as a therapy in ischemic tissue repair. Incubation of BMPACs with these peptide nanofibers in vitro significantly attenuated apoptosis while enhancing proliferation and adhesion. Pro-angiogenic function was enhanced, as cells readily formed tubes. These effects were, in part, mediated via p38, and p44/p42 MAP kinases, which are downstream pathways of focal adhesion kinase. In a murine model of hind limb ischemia, an intramuscular injection of BMPACs within this bioactive peptide nanofiber matrix resulted in greater retention of cells, enhanced capillary density, increased limb perfusion, reduced necrosis/amputation, and preserved function of the ischemic limb compared to treatment with cells alone. This self-assembling, bioactive peptide nanofiber matrix presenting an integrin-binding domain of fibronectin improves regenerative efficacy of cell-based strategies in ischemic tissue by enhancing cell survival, retention, and reparative functions.
authors.affiliation: Feinberg Cardiovascular Research Institute, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA; Department of Cardiology and Angiology, Hannover Medical School, Hannover, Germany.
authors.forename: Jörn
authors.initials: J
authors.lastname: Tongers
authors.affiliation: Institute for Bionanotechnology in Medicine, Department of Medicine, Northwestern University, Chicago, IL, USA.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Webber
authors.affiliation: Feinberg Cardiovascular Research Institute, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
authors.forename: Erin E
authors.initials: EE
authors.lastname: Vaughan
authors.affiliation: Institute for Bionanotechnology in Medicine, Department of Medicine, Northwestern University, Chicago, IL, USA.
authors.forename: Eduard
authors.initials: E
authors.lastname: Sleep
authors.affiliation: Feinberg Cardiovascular Research Institute, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
authors.forename: Marie-Ange
authors.initials: MA
authors.lastname: Renault
authors.affiliation: Feinberg Cardiovascular Research Institute, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
authors.forename: Jerome G
authors.initials: JG
authors.lastname: Roncalli
authors.affiliation: Feinberg Cardiovascular Research Institute, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
authors.forename: Ekaterina
authors.initials: E
authors.lastname: Klyachko
authors.affiliation: Feinberg Cardiovascular Research Institute, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
authors.forename: Tina
authors.initials: T
authors.lastname: Thorne
authors.affiliation: Feinberg Cardiovascular Research Institute, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
authors.forename: Yang
authors.initials: Y
authors.lastname: Yu
authors.affiliation: Feinberg Cardiovascular Research Institute, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA; Department of Cardiology and Angiology, Hannover Medical School, Hannover, Germany.
authors.forename: Katja-Theres
authors.initials: KT
authors.lastname: Marquardt
authors.affiliation: Feinberg Cardiovascular Research Institute, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
authors.forename: Christine E
authors.initials: CE
authors.lastname: Kamide
authors.affiliation: Feinberg Cardiovascular Research Institute, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
authors.forename: Aiko
authors.initials: A
authors.lastname: Ito
authors.affiliation: Feinberg Cardiovascular Research Institute, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
authors.forename: Sol
authors.initials: S
authors.lastname: Misener
authors.affiliation: Feinberg Cardiovascular Research Institute, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
authors.forename: Meredith
authors.initials: M
authors.lastname: Millay
authors.affiliation: Feinberg Cardiovascular Research Institute, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
authors.forename: Ting
authors.initials: T
authors.lastname: Liu
authors.affiliation: Feinberg Cardiovascular Research Institute, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
authors.forename: Kentaro
authors.initials: K
authors.lastname: Jujo
authors.affiliation: Feinberg Cardiovascular Research Institute, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
authors.forename: Gangjian
authors.initials: G
authors.lastname: Qin
authors.affiliation: Feinberg Cardiovascular Research Institute, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
authors.forename: Douglas W
authors.initials: DW
authors.lastname: Losordo
authors.affiliation: Institute for Bionanotechnology in Medicine, Department of Medicine, Northwestern University, Chicago, IL, USA; Department of Materials Science and Engineering, Department of Chemistry, Northwestern University, Evanston, IL, USA. Electronic address: s-stupp@northwestern.edu.
authors.forename: Samuel I
authors.initials: SI
authors.lastname: Stupp
authors.affiliation: Feinberg Cardiovascular Research Institute, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA; Center for Translational Medicine, Temple University School of Medicine, Philadelphia, PA, USA. Electronic address: Raj.kishore@temple.edu.
authors.forename: Raj
authors.initials: R
authors.lastname: Kishore
mesh_terms: D000818:Animals; D001672:Biocompatible Materials; D001854:Bone Marrow Cells / Q000166:cytology* / Q000378:metabolism; D002470:Cell Survival; D064987:Cell- and Tissue-Based Therapy / Q000379:methods; D000939:Epitopes / Q000737:chemistry / Q000378:metabolism*; D005353:Fibronectins / Q000737:chemistry / Q000378:metabolism*; D015870:Gene Expression; D006614:Hindlimb / Q000098:blood supply / Q000187:drug effects / Q000293:injuries; D016023:Integrins / Q000378:metabolism; D007511:Ischemia / Q000473:pathology / Q000628:therapy*; D008297:Male; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000235:genetics / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics / Q000378:metabolism; D057139:Nanofibers / Q000008:administration & dosage* / Q000737:chemistry; D018919:Neovascularization, Physiologic; D010455:Peptides / Q000008:administration & dosage* / Q000138:chemical synthesis / Q000378:metabolism; D011485:Protein Binding; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: D001672:Biocompatible Materials; D000939:Epitopes; D005353:Fibronectins; D016023:Integrins; D010455:Peptides; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048051:p38 Mitogen-Activated Protein Kinases
keywords: Angiogenesis; Biomaterials; Cell therapy; Microcirculation; Nanomedicine; Regenerative medicine