Mesenchymal cell transplantation and myocardial remodeling after myocardial infarction.
BACKGROUND
Targeted delivery of mesenchymal precursor cells (MPCs) can modify left ventricular (LV) cellular and extracellular remodeling after myocardial infarction (MI). However, whether and to what degree LV remodeling may be affected by MPC injection post-MI, and whether these effects are concentration-dependent, remain unknown.


RESULTS
Allogeneic MPCs were expanded from sheep bone marrow, and direct intramyocardial injection was performed within the borderzone region 1 hour after MI induction (coronary ligation) in sheep at the following concentrations: 25x10(6) (25 M, n=7), 75x10(6) (75 M, n=7), 225x10(6) (225 M, n=10), 450x10(6) (450 M, n=8), and MPC free media only (MI Only, n=14). LV end diastolic volume increased in all groups but was attenuated in the 25 and 75 M groups. Collagen content within the borderzone region was increased in the MI Only, 225, and 450 M groups, whereas plasma ICTP, an index of collagen degradation, was highest in the 25 M group. Within the borderzone region matrix metalloproteinases (MMPs) and MMP tissue inhibitors (TIMPs) also changed in a MPC concentration-dependent manner. For example, borderzone levels of MMP-9 were highest in the 25 M group when compared to the MI Only and other MPC treatment group values.


CONCLUSIONS
MPC injection altered collagen dynamics, MMP, and TIMP levels in a concentration-dependent manner, and thereby influenced indices of post-MI LV remodeling. However, the greatest effects with respect to post-MI remodeling were identified at lower MPC concentrations, thus suggesting a therapeutic threshold exists for this particular cell therapy.
Dixon
Jennifer A
JA
Medical University of South Carolina and Ralph H. Johnson Veterans Affairs Medical Center, Charleston, USA.
Gorman
Robert C
RC
Stroud
Robert E
RE
Bouges
Shenikqua
S
Hirotsugu
Hamamoto
H
Gorman
Joseph H
JH
Martens
Timothy P
TP
Itescu
Silviu
S
Schuster
Michael D
MD
Plappert
Theodore
T
St John-Sutton
Martin G
MG
Spinale
Francis G
FG
D000818:Animals; D003094:Collagen / Q000378:metabolism; D005260:Female; D020782:Matrix Metalloproteinases / Q000032:analysis; D045164:Mesenchymal Stem Cell Transplantation; D009203:Myocardial Infarction / Q000473:pathology / Q000503:physiopathology / Q000628:therapy*; D012756:Sheep; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000032:analysis; D016277:Ventricular Function, Left; D020257:Ventricular Remodeling
D019715:Tissue Inhibitor of Metalloproteinase-1; D003094:Collagen; D020782:Matrix Metalloproteinases