Enhanced potency of cell-based therapy for ischemic tissue repair using an injectable bioactive epitope presenting nanofiber support matrix

• Published in: Journal of molecular and cellular cardiology 2014-09, Vol.74, p.231-239
• Main Authors: Tongers, Jörn, Webber, Matthew J, Vaughan, Erin E, Sleep, Eduard, Renault, Marie-Ange, Roncalli, Jerome G, Klyachko, Ekaterina, Thorne, Tina, Yu, Yang, Marquardt, Katja-Theres, Kamide, Christine E, Ito, Aiko, Misener, Sol, Millay, Meredith, Liu, Ting, Jujo, Kentaro, Qin, Gangjian, Losordo, Douglas W, Stupp, Samuel I, Kishore, Raj
• Format: Article
• Language: English
• Subjects: Angiogenesis; Animals; Biocompatible Materials; Biomaterials; Bone Marrow Cells - cytology; Bone Marrow Cells - metabolism; Cardiovascular; Cell Survival; Cell therapy; Cell- and Tissue-Based Therapy - methods; Epitopes - chemistry; Epitopes - metabolism; Fibronectins - chemistry; Fibronectins - metabolism; Gene Expression; Hindlimb - blood supply; Hindlimb - drug effects; Hindlimb - injuries; Integrins - metabolism; Ischemia - pathology; Ischemia - therapy; Male; Mice; Microcirculation; Mitogen-Activated Protein Kinase 1 - genetics; Mitogen-Activated Protein Kinase 1 - metabolism; Mitogen-Activated Protein Kinase 3 - genetics; Mitogen-Activated Protein Kinase 3 - metabolism; Nanofibers - administration & dosage; Nanofibers - chemistry; Nanomedicine; Neovascularization, Physiologic; p38 Mitogen-Activated Protein Kinases - genetics; p38 Mitogen-Activated Protein Kinases - metabolism; Peptides - administration & dosage; Peptides - chemical synthesis; Peptides - metabolism; Protein Binding; Regenerative medicine
• ISSN: 0022-2828; 1095-8584
• DOI: 10.1016/j.yjmcc.2014.05.017

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.