title: Repeated doses of cardiac mesenchymal cells are therapeutically superior to a single dose in mice with old myocardial infarction.
abstract: We have recently demonstrated that repeated administrations of c-kitPOScardiac progenitor cells (CPCs) have cumulative beneficial effects in rats with old myocardial infarction (MI), resulting in markedly greater improvement in left ventricular (LV) function compared with a single administration. To determine whether this paradigm applies to other species and cell types, mice with a 3-week-old MI received one or three doses of cardiac mesenchymal cells (CMCs), a novel cell type that we have recently described. CMCs or vehicle were infused percutaneously into the LV cavity, 14 days apart. Compared with vehicle-treated mice, the single-dose group exhibited improved LV ejection fraction (EF) after the 1st infusion (consisting of CMCs) but not after the 2nd and 3rd (vehicle). In contrast, in the multiple-dose group, LV EF improved after each CMC infusion, so that at the end of the study, LV EF averaged 35.5 ± 0.7% vs. 32.7 ± 0.6% in the single-dose group (P < 0.05). The multiple-dose group also exhibited less collagen in the non-infarcted region vs. the single-dose group. Engraftment and differentiation of CMCs were negligible in both groups, indicating paracrine effects. These results demonstrate that, in mice with ischemic cardiomyopathy, the beneficial effects of three doses of CMCs are significantly greater than those of one dose, supporting the concept that multiple treatments are necessary to properly evaluate the full therapeutic potential of cell therapy. Thus, the repeated-treatment paradigm is not limited to c-kitPOSCPCs or to rats, but applies to other cell types and species. The generalizability of this concept dramatically augments its significance.
authors.affiliation: Institute of Molecular Cardiology, University of Louisville School of Medicine, Louisville, KY, USA.
authors.forename: Yiru
authors.identifier: http://orcid.org/0000-0002-0614-9899
authors.initials: Y
authors.lastname: Guo
authors.affiliation: Institute of Molecular Cardiology, University of Louisville School of Medicine, Louisville, KY, USA.
authors.forename: Marcin
authors.initials: M
authors.lastname: Wysoczynski
authors.affiliation: Institute of Molecular Cardiology, University of Louisville School of Medicine, Louisville, KY, USA.
authors.forename: Yibing
authors.initials: Y
authors.lastname: Nong
authors.affiliation: Institute of Molecular Cardiology, University of Louisville School of Medicine, Louisville, KY, USA.
authors.forename: Alex
authors.initials: A
authors.lastname: Tomlin
authors.affiliation: Institute of Molecular Cardiology, University of Louisville School of Medicine, Louisville, KY, USA.
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Zhu
authors.affiliation: Institute of Molecular Cardiology, University of Louisville School of Medicine, Louisville, KY, USA.
authors.forename: Anna M
authors.initials: AM
authors.lastname: Gumpert
authors.affiliation: Institute of Molecular Cardiology, University of Louisville School of Medicine, Louisville, KY, USA.
authors.forename: Marjan
authors.initials: M
authors.lastname: Nasr
authors.affiliation: Institute of Molecular Cardiology, University of Louisville School of Medicine, Louisville, KY, USA.
authors.forename: Senthikumar
authors.initials: S
authors.lastname: Muthusamy
authors.affiliation: Institute of Molecular Cardiology, University of Louisville School of Medicine, Louisville, KY, USA.
authors.forename: Hong
authors.initials: H
authors.lastname: Li
authors.affiliation: Institute of Molecular Cardiology, University of Louisville School of Medicine, Louisville, KY, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Book
authors.affiliation: Institute of Molecular Cardiology, University of Louisville School of Medicine, Louisville, KY, USA.
authors.forename: Abdur
authors.initials: A
authors.lastname: Khan
authors.affiliation: Institute of Molecular Cardiology, University of Louisville School of Medicine, Louisville, KY, USA.
authors.forename: Kyung U
authors.initials: KU
authors.lastname: Hong
authors.affiliation: Institute of Molecular Cardiology, University of Louisville School of Medicine, Louisville, KY, USA.
authors.forename: Qianhong
authors.initials: Q
authors.lastname: Li
authors.affiliation: Institute of Molecular Cardiology, University of Louisville School of Medicine, Louisville, KY, USA. rbolli@louisville.edu.
authors.forename: Roberto
authors.initials: R
authors.lastname: Bolli
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D004452:Echocardiography; D005260:Female; D007150:Immunohistochemistry; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation / Q000379:methods*; D059630:Mesenchymal Stem Cells / Q000166:cytology; D051379:Mice; D008810:Mice, Inbred C57BL; D009203:Myocardial Infarction; D032383:Myocytes, Cardiac / Q000166:cytology; D011897:Random Allocation
keywords: Cell therapy; Ischemic cardiomyopathy; Progenitor cells; Stem cells