TY - JOUR
T1 - Enhanced potency of cell-based therapy for ischemic tissue repair using an injectable bioactive epitope presenting nanofiber support matrix
AU - Tongers, Jörn
AU - Webber, Matthew J.
AU - Vaughan, Erin E.
AU - Sleep, Eduard
AU - Renault, Marie Ange
AU - Roncalli, Jerome G.
AU - Klyachko, Ekaterina
AU - Thorne, Tina
AU - Yu, Yang
AU - Marquardt, Katja Theres
AU - Kamide, Christine E.
AU - Ito, Aiko
AU - Misener, Sol
AU - Millay, Meredith
AU - Liu, Ting
AU - Jujo, Kentaro
AU - Qin, Gangjian
AU - Losordo, Douglas W.
AU - Stupp, Samuel I.
AU - Kishore, Raj
N1 - Funding Information:
This work was supported in part by funding from the National Institute of Health , specifically grants HL091983 , HL105597 , HL095874 , HL053354 , HL108795 and EB003806 . JT was supported by the American Heart Association award 0920094G and the German Heart Foundation award S/03/06 . ES was supported by the IBNAM-Baxter Early Career Development Award , between . Baxter Healthcare Corporation and Northwestern University under Agreement dated 9/28/11 and this project was additionally supported by an IBNAM-Baxter Research Incubator grant between . Baxter Healthcare Corporation and Northwestern University under Agreement dated 5/27/09, and a Northwestern Memorial Foundation Dixon Translational Research Grant Initiative Award . We thank Xiaomin Zhang and Dixon B. Kaufman, formerly from the department of Transplant Surgery at Northwestern Memorial Hospital, for technical support with bioluminescent imaging.
PY - 2014/9
Y1 - 2014/9
N2 - 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.
AB - 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.
KW - Angiogenesis
KW - Biomaterials
KW - Cell therapy
KW - Microcirculation
KW - Nanomedicine
KW - Regenerative medicine
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U2 - 10.1016/j.yjmcc.2014.05.017
DO - 10.1016/j.yjmcc.2014.05.017
M3 - Article
C2 - 25009075
AN - SCOPUS:84904726425
VL - 74
SP - 231
EP - 239
JO - Journal of Molecular and Cellular Cardiology
JF - Journal of Molecular and Cellular Cardiology
SN - 0022-2828
ER -