Allogeneic mesenchymal precursor cell therapy to limit remodeling after myocardial infarction: the effect of cell dosage.
BACKGROUND
This experiment assessed the dose-dependent effect of a unique allogeneic STRO-3-positive mesenchymal precursor cell (MPC) on postinfarction left ventricular (LV) remodeling. The MPCs were administered in a manner that would simulate an off-the-self, early postinfarction, preventative approach to cardiac cell therapy in a sheep transmural myocardial infarct (MI) model.


METHODS
Allogeneic MPCs were isolated from male crossbred sheep. Forty-six female sheep underwent coronary ligation to produce a transmural LV anteroapical infarction. One hour after infarction, the borderzone myocardium received an injection of 25, 75, 225, or 450 x 10(6) MPCs, or cell medium. Echocardiography was performed at 4 and 8 weeks after MI to quantify LV end-diastolic (LVEDV) and end-systolic volumes (LVESV), ejection fraction (EF), and infarct expansion. CD31 and smooth muscle actin (SMA) immunohistochemical staining was performed on infarct and borderzone specimens to quantify vascular density.


RESULTS
Compared with controls, low-dose (25 and 75 x 10(6) cells) MPC treatment significantly attenuated infarct expansion and increases in LVEDV and LVESV. EF was improved at all cell doses. CD31 and SMA immunohistochemical staining demonstrated increased vascular density in the borderzone only at the lower cell doses. There was no evidence of myocardial regeneration within the infarct.


CONCLUSIONS
Allogeneic STRO-3 positive MPCs attenuate the remodeling response to transmural MI in a clinically relevant large-animal model. This effect is associated with vasculogenesis and arteriogenesis within the borderzone and infarct and is most pronounced at lower cell doses.
Hamamoto
Hirotsugu
H
Department of Surgery, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.
Gorman
Joseph H
JH
Ryan
Liam P
LP
Hinmon
Robin
R
Martens
Timothy P
TP
Schuster
Michael D
MD
Plappert
Theodore
T
Kiupel
Matti
M
St John-Sutton
Martin G
MG
Itescu
Silviu
S
Gorman
Robert C
RC
D000818:Animals; D002452:Cell Count; D005260:Female; D045164:Mesenchymal Stem Cell Transplantation / Q000379:methods / Q000706:statistics & numerical data; D009203:Myocardial Infarction / Q000150:complications* / Q000473:pathology; D012756:Sheep; D020257:Ventricular Remodeling