title: Transplantation of expanded bone marrow-derived very small embryonic-like stem cells (VSEL-SCs) improves left ventricular function and remodelling after myocardial infarction.
abstract: Adult bone marrow-derived very small embryonic-like stem cells (VSEL-SCs) exhibit a Sca-1(+)/Lin(-)/CD45(-) phenotype and can differentiate into various cell types, including cardiomyocytes and endothelial cells. We have previously reported that transplantation of a small number (1 × 10(6)) of freshly isolated, non-expanded VSEL-SCs into infarcted mouse hearts resulted in improved left ventricular (LV) function and anatomy. Clinical translation, however, will require large numbers of cells. Because the frequency of VSEL-SCs in the marrow is very low, we examined whether VSEL-SCs can be expanded in culture without loss of therapeutic efficacy. Mice underwent a 30 min. coronary occlusion followed by reperfusion and, 48 hrs later, received an intramyocardial injection of vehicle (group I, n = 11), 1 × 10(5) enhanced green fluorescent protein (EGFP)-labelled expanded untreated VSEL-SCs (group II, n = 7), or 1 × 10(5) EGFP-labelled expanded VSEL-SCs pre-incubated in a cardiogenic medium (group III, n = 8). At 35 days after myocardial infarction (MI), mice treated with pre-incubated VSEL-SCs exhibited better global and regional LV systolic function and less LV hypertrophy compared with vehicle-treated controls. In contrast, transplantation of expanded but untreated VSEL-SCs did not produce appreciable reparative benefits. Scattered EGFP(+) cells expressing α-sarcomeric actin, platelet endothelial cell adhesion molecule (PECAM)-1, or von Willebrand factor were present in VSEL-SC-treated mice, but their numbers were very small. No tumour formation was observed. We conclude that VSEL-SCs expanded in culture retain the ability to alleviate LV dysfunction and remodelling after a reperfused MI provided that they are exposed to a combination of cardiomyogenic growth factors and cytokines prior to transplantation. Counter intuitively, the mechanism whereby such pre-incubation confers therapeutic efficacy does not involve differentiation into new cardiac cells. These results support the potential therapeutic utility of VSEL-SCs for cardiac repair.
authors.affiliation: Institute of Molecular Cardiology, University of Louisville, Louisville, KY, USA.
authors.forename: Ewa K
authors.initials: EK
authors.lastname: Zuba-Surma
authors.forename: Yiru
authors.initials: Y
authors.lastname: Guo
authors.forename: Hisham
authors.initials: H
authors.lastname: Taher
authors.forename: Santosh K
authors.initials: SK
authors.lastname: Sanganalmath
authors.forename: Greg
authors.initials: G
authors.lastname: Hunt
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Vincent
authors.forename: Magda
authors.initials: M
authors.lastname: Kucia
authors.forename: Ahmed
authors.initials: A
authors.lastname: Abdel-Latif
authors.forename: Xian-Liang
authors.initials: XL
authors.lastname: Tang
authors.forename: Mariusz Z
authors.initials: MZ
authors.lastname: Ratajczak
authors.forename: Buddhadeb
authors.initials: B
authors.lastname: Dawn
authors.forename: Roberto
authors.initials: R
authors.lastname: Bolli
mesh_terms: D000818:Animals; D001853:Bone Marrow / Q000502:physiology; D018929:Cell Culture Techniques; D049109:Cell Proliferation / Q000187:drug effects*; D054059:Coronary Occlusion / Q000150:complications; D003470:Culture Media; D016207:Cytokines / Q000494:pharmacology; D004195:Disease Models, Animal; D053595:Embryonic Stem Cells / Q000166:cytology / Q000637:transplantation; D049452:Green Fluorescent Proteins / Q000032:analysis; D007273:Injections, Intramuscular / Q000379:methods*; D036341:Intercellular Signaling Peptides and Proteins / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009203:Myocardial Infarction / Q000209:etiology / Q000473:pathology / Q000503:physiopathology / Q000628:therapy*; D009206:Myocardium / Q000473:pathology*; D033581:Stem Cell Transplantation / Q000379:methods*; D016277:Ventricular Function, Left; D020257:Ventricular Remodeling
chemical_list: D003470:Culture Media; D016207:Cytokines; D036341:Intercellular Signaling Peptides and Proteins; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins