Pretreatment of adult bone marrow mesenchymal stem cells with cardiomyogenic growth factors and repair of the chronically infarcted myocardium.
The in vivo cardiac differentiation and functional effects of unmodified adult bone marrow mesenchymal stem cells (MSCs) after myocardial infarction (MI) is controversial. We postulated that ex vivo pretreatment of autologous MSCs using cardiomyogenic growth factors will lead to cardiomyogenic specification and will result in superior biological and functional effects on cardiac regeneration of chronically infarcted myocardium. We used a chronic dog MI model generated by ligation of the coronary artery (n = 30). Autologous dog bone marrow MSCs were isolated, culture expanded, and specified into a cardiac lineage by adding growth factors, including basic FGF, IGF-1, and bone morphogenetic protein-2. Dogs underwent cell injection >8 wk after the infarction and were randomized into two groups. Group A dogs (n = 20) received MSCs specified with growth factors (147 +/- 96 x 10(6)), and group B (n = 10) received unmodified MSCs (168 +/- 24 x 10(6)). After the growth factor treatment, MSCs stained positive for the early muscle and cardiac markers desmin, antimyocyte enhancer factor-2, and Nkx2-5. In group A dogs, prespecified MSCs colocalized with troponin I and cardiac myosin. At 12 wk, group A dogs showed a significantly larger increase in regional wall thickening of the infarcted territory (from 22 +/- 8 to 32 +/- 6% in group A; P < 0.05 vs. baseline and group B, and from 19 +/- 7 to 21 +/- 7% in group B, respectively) and a decrease in the wall motion score index (from 1.60 +/- 0.05 to 1.35 +/- 0.03 in group A; P < 0.05 vs. baseline and group B, and from 1.58 +/- 0.07 vs. 1.56 +/- 0.08 in group B, respectively). The biological ex vivo cardiomyogenic specification of adult MSCs before their transplantation is feasible and appears to improve their in vivo cardiac differentiation as well as the functional recovery in a dog model of the chronically infarcted myocardium.
Bartunek
Jozef
J
Cardiovascular Center and Cardiovascular Research Center, Aalst, Moorselbaan 164, 9300 Aalst, Belgium. jozef.bartunek@olvz-aalst.be
Croissant
Jeffrey D
JD
Wijns
William
W
Gofflot
Stephanie
S
de Lavareille
Aurore
A
Vanderheyden
Marc
M
Kaluzhny
Yulia
Y
Mazouz
Naïma
N
Willemsen
Philippe
P
Penicka
Martin
M
Mathieu
Myrielle
M
Homsy
Christian
C
De Bruyne
Bernard
B
McEntee
Kathleen
K
Lee
Ike W
IW
Heyndrickx
Guy R
GR
D053687:Adult Stem Cells / Q000187:drug effects*; D000818:Animals; D001854:Bone Marrow Cells / Q000187:drug effects*; D019485:Bone Morphogenetic Proteins / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects; D019070:Cell Lineage / Q000187:drug effects; D002478:Cells, Cultured; D002908:Chronic Disease; D004195:Disease Models, Animal; D004285:Dogs; D005346:Fibroblast Growth Factors / Q000494:pharmacology; D006352:Heart Ventricles / Q000473:pathology; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology; D036341:Intercellular Signaling Peptides and Proteins / Q000494:pharmacology*; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000187:drug effects; D009203:Myocardial Infarction / Q000473:pathology / Q000503:physiopathology / Q000601:surgery*; D011897:Random Allocation; D020127:Recovery of Function; D013997:Time Factors; D014182:Transplantation, Autologous; D016277:Ventricular Function, Left
D019485:Bone Morphogenetic Proteins; D036341:Intercellular Signaling Peptides and Proteins; D005346:Fibroblast Growth Factors; D007334:Insulin-Like Growth Factor I