title: Spherical bullet formation via E-cadherin promotes therapeutic potency of mesenchymal stem cells derived from human umbilical cord blood for myocardial infarction.
abstract: The beneficial effects of stem cells in clinical applications to date have been modest, and studies have reported that poor engraftment might be an important reason. As a strategy to overcome such a hurdle, we developed the spheroid three dimensional (3D) bullet as a delivery method for human umbilical cord blood-derived mesenchymal stem cells (hUCB-MSCs) through the maintenance of cell-cell interactions without additional xenofactors, cytokines, or matrix. We made spheroid 3D-bullets from hUCB-MSCs at 24 hours' anchorage-deprived suspension culture. To investigate the in vivo therapeutic efficacy of 3D-bullets, we used rat myocardial infarction (MI) model. Transplantation of 3D-bullet was better than that of single cells from monolayer culture or from 3D-bullet in improving left ventricular (LV) contractility [LV ejection fraction (LVEF) or LV fractional shortening (LVFS)] and preventing pathologic LV dilatation [LV end-systolic diameter (LVESD) or LV end-diastolic diameter (LVEDD)] at 8 weeks. In the mechanism study of 3D-bullet formation, we found that calcium-dependent cell-cell interaction was essential and that E-cadherin is a key inducer mediating hUCB-MSC 3D-bullet formation among several calcium-dependent adhesion molecules which were nominated as candidates after cDNA array analysis. In more specific experiments with E-cadherin overexpression using adenoviral vector or with E-cadherin neutralization using blocking antibody, we found that E-cadherin regulates vascular endothelial growth factor (VEGF) secretion via extracellular signal-regulated kinase (ERK)/v-akt murine thymoma viral oncogene homolog1 (AKT) pathways. During formation of spheroid 3D-bullets, activation of E-cadherin in association with cell-cell interaction turns on ERK/AKT signaling pathway that are essential to proliferative and paracrine activity of MSCs leading to the enhanced therapeutic efficacy.
authors.affiliation: National Research Laboratory for Stem Cell Niche and IRICT, Seoul National University Hospital, Seoul, Korea.
authors.forename: Eun Ju
authors.initials: EJ
authors.lastname: Lee
authors.forename: Sung Jung
authors.initials: SJ
authors.lastname: Park
authors.forename: Soo Kyoung
authors.initials: SK
authors.lastname: Kang
authors.forename: Gi-Hwan
authors.initials: GH
authors.lastname: Kim
authors.forename: Hyun-Jae
authors.initials: HJ
authors.lastname: Kang
authors.forename: Sae-Won
authors.initials: SW
authors.lastname: Lee
authors.forename: Hong Bae
authors.initials: HB
authors.lastname: Jeon
authors.forename: Hyo-Soo
authors.initials: HS
authors.lastname: Kim
mesh_terms: D000818:Animals; D015820:Cadherins / Q000378:metabolism*; D000229:Dependovirus / Q000235:genetics; D004195:Disease Models, Animal; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005312:Fetal Blood; D005822:Genetic Vectors; D006801:Humans; D045164:Mesenchymal Stem Cell Transplantation / Q000379:methods*; D059630:Mesenchymal Stem Cells / Q000378:metabolism*; D008863:Microspheres; D009203:Myocardial Infarction / Q000628:therapy*; D018919:Neovascularization, Physiologic; D051058:Oncogene Protein v-akt / Q000378:metabolism; D051381:Rats; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D016277:Ventricular Function, Left; D020257:Ventricular Remodeling
chemical_list: D015820:Cadherins; D042461:Vascular Endothelial Growth Factor A; D051058:Oncogene Protein v-akt; D048049:Extracellular Signal-Regulated MAP Kinases