title: Grafts enriched with subamnion-cord-lining mesenchymal stem cell angiogenic spheroids induce post-ischemic myocardial revascularization and preserve cardiac function in failing rat hearts.
abstract: A crucial question in post-ischemic cell therapy refers to the ideal method of cell delivery to the heart. We hypothesized that epicardial implantation of subamnion-cord-lining mesenchymal stem cells (CL-MSC) angiogenic spheroids embedded within fibrin grafts (SASG) facilitates donor cell survival and enhances cardiac function in failing rat hearts. Furthermore, we compared the efficacy of this approach applied through two delivery methods. Spheroids made of 1.5×10(4) human CL-MSC coated with 2×10(3) human umbilical vein endothelial cells were self-assembled in hanging drops. SASG were constructed by embedding 150 spheroids in fibrin matrix. Except for untreated rats (MI, n=8), grafts were implanted 2 weeks after myocardial infarction upon confirmation of ensued heart failure through thoracotomy: SASG (n=8) and fibrin graft (FG, n=8); or video-assisted thoracoscopic surgery (VATS): SASG-VATS (n=8) and FG-VATS (n=7). In vivo CL-MSC survival was comparable between both SASG-treated groups throughout the study. SASG and SASG-VATS animals had decreased left ventricular end-diastolic pressure relative to untreated animals, and increased fractional shortening compared to MI and FG controls, 4 weeks after treatment. A 14.1% and 6.2% enhancement in ejection fraction from week 2 to 6 after injury was observed in SASG/SASG-VATS, paralleled by improvement in cardiac output. Treated hearts had smaller scar size, and more blood vessels than MI, while donor CL-MSC contributed to arteriogenesis within the graft and infarct areas. Taken together, our data suggest that SASG treatment has the potential to restore failing hearts by preserving cardiac function and inducing myocardial revascularization, while attenuating cardiac fibrosis. Furthermore, we introduce a method for minimally invasive in situ graft assembly.
authors.affiliation: 1 Department of Surgery, Yong Loo Lin School of Medicine, National University of Singapore , Singapore, Singapore .
authors.forename: Eliana C
authors.initials: EC
authors.lastname: Martinez
authors.forename: Duc-Thang
authors.initials: DT
authors.lastname: Vu
authors.forename: Jing
authors.initials: J
authors.lastname: Wang
authors.forename: Shera
authors.initials: S
authors.lastname: Lilyanna
authors.forename: Lieng H
authors.initials: LH
authors.lastname: Ling
authors.forename: Shu U
authors.initials: SU
authors.lastname: Gan
authors.forename: Ai Li
authors.initials: AL
authors.lastname: Tan
authors.forename: Thang T
authors.initials: TT
authors.lastname: Phan
authors.forename: Chuen N
authors.initials: CN
authors.lastname: Lee
authors.forename: Theo
authors.initials: T
authors.lastname: Kofidis
mesh_terms: D000650:Amnion / Q000166:cytology*; D000818:Animals; D004195:Disease Models, Animal; D006333:Heart Failure / Q000150:complications / Q000503:physiopathology / Q000601:surgery / Q000628:therapy; D006334:Heart Function Tests; D061307:Human Umbilical Vein Endothelial Cells / Q000166:cytology; D006801:Humans; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000166:cytology; D009203:Myocardial Infarction / Q000150:complications / Q000503:physiopathology / Q000601:surgery / Q000628:therapy; D017202:Myocardial Ischemia / Q000150:complications / Q000503:physiopathology* / Q000601:surgery / Q000628:therapy*; D009204:Myocardial Revascularization; D009206:Myocardium / Q000473:pathology; D018919:Neovascularization, Physiologic; D010641:Phenotype; D055503:Protein Multimerization; D051381:Rats; D011923:Rats, Nude; D018874:Spheroids, Cellular / Q000166:cytology; D020775:Thoracic Surgery, Video-Assisted; D013908:Thoracotomy; D014470:Umbilical Cord / Q000166:cytology*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D020257:Ventricular Remodeling
chemical_list: D042461:Vascular Endothelial Growth Factor A