title: PlGF-MMP9-engineered iPS cells supported on a PEG-fibrinogen hydrogel scaffold possess an enhanced capacity to repair damaged myocardium.
abstract: Cell-based regenerative therapies are significantly improved by engineering allografts to express factors that increase vascularization and engraftment, such as placental growth factor (PlGF) and matrix metalloproteinase 9 (MMP9). Moreover, the seeding of therapeutic cells onto a suitable scaffold is of utmost importance for tissue regeneration. On these premises, we sought to assess the reparative potential of induced pluripotent stem (iPS) cells bioengineered to secrete PlGF or MMP9 and delivered to infarcted myocardium upon a poly(ethylene glycol)-fibrinogen scaffold. When assessing optimal stiffness of the PEG-fibrinogen (PF) scaffold, we found that the appearance of contracting cells after cardiogenic induction was accelerated on the support designed with an intermediate stiffness. Revascularization and hemodynamic parameters of infarcted mouse heart were significantly improved by injection into the infarct of this optimized PF scaffold seeded with both MiPS (iPS cells engineered to secrete MMP9) and PiPS (iPS cells engineered to secrete PlGF) cells as compared with nonengineered cells or PF alone. Importantly, allograft-derived cells and host myocardium were functionally integrated. Therefore, survival and integration of allografts in the ischemic heart can be significantly improved with the use of therapeutic cells bioengineered to secrete MMP9 and PlGF and encapsulated within an injectable PF hydrogel having an optimized stiffness.
authors: 1] Istituto Ricovero Cura Carattere Scientifico MultiMedica, Milan, Italy [2] Cell Biology and Neurobiology Institute, National Research Council of Italy (CNR), Rome, Italy.
authors: C
authors: C
authors: Bearzi
authors: Istituto Ricovero Cura Carattere Scientifico MultiMedica, Milan, Italy.
authors: C
authors: C
authors: Gargioli
authors: Istituto Ricovero Cura Carattere Scientifico MultiMedica, Milan, Italy.
authors: D
authors: D
authors: Baci
authors: Istituto Ricovero Cura Carattere Scientifico MultiMedica, Milan, Italy.
authors: O
authors: O
authors: Fortunato
authors: Faculty of Biomedical Engineering, Technion-Israel Institute of Technology, Haifa, Israel.
authors: K
authors: K
authors: Shapira-Schweitzer
authors: Faculty of Biomedical Engineering, Technion-Israel Institute of Technology, Haifa, Israel.
authors: O
authors: O
authors: Kossover
authors: Humanitas Clinical and Research Center, Rozzano, Milan, Italy.
authors: M V G
authors: MV
authors: Latronico
authors: Faculty of Biomedical Engineering, Technion-Israel Institute of Technology, Haifa, Israel.
authors: D
authors: D
authors: Seliktar
authors: Humanitas Clinical and Research Center, Rozzano, Milan, Italy.
authors: G
authors: G
authors: Condorelli
authors: 1] Istituto Ricovero Cura Carattere Scientifico MultiMedica, Milan, Italy [2] Cell Biology and Neurobiology Institute, National Research Council of Italy (CNR), Rome, Italy.
authors: R
authors: R
authors: Rizzi
mesh_terms: D000818:Animals; D002470:Cell Survival; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005260:Female; D005340:Fibrinogen / Q000737:chemistry*; D005818:Genetic Engineering; D006439:Hemodynamics; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000201:enzymology / Q000637:transplantation*; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009200:Myocardial Contraction; D009203:Myocardial Infarction / Q000201:enzymology / Q000235:genetics / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D009206:Myocardium / Q000201:enzymology* / Q000473:pathology; D032383:Myocytes, Cardiac / Q000201:enzymology / Q000637:transplantation*; D018919:Neovascularization, Physiologic; D000072483:Placenta Growth Factor; D011092:Polyethylene Glycols / Q000737:chemistry*; D011257:Pregnancy Proteins / Q000235:genetics / Q000378:metabolism*; D020127:Recovery of Function; D012038:Regeneration; D013997:Time Factors; D023822:Tissue Engineering / Q000379:methods*; D054457:Tissue Scaffolds; D014161:Transduction, Genetic; D014162:Transfection
chemical_list: C000608036:PGF protein, human; C000608037:Pgf protein, mouse; D011257:Pregnancy Proteins; D000072483:Placenta Growth Factor; D011092:Polyethylene Glycols; D005340:Fibrinogen; D020780:Matrix Metalloproteinase 9