Reduction of myocardial infarct size by human mesenchymal stem cell conditioned medium.
Although paracrine effects of mesenchymal stem cells (MSCs) have been suggested previously, cardioprotection by human MSC secretions has never been demonstrated. Human MSC-conditioned medium (CM) was collected by following a clinically compliant protocol. In a porcine model of ischemia and reperfusion injury, intravenous and intracoronary MSC-CM treatment significantly reduced myocardial nuclear oxidative stress as determined by immunostaining for 8-hydroxy-2'-deoxyguanosine. In addition, expression levels of phospho-SMAD2 and active caspase 3 were diminished following CM treatment, suggesting that TGF-beta signaling and apoptosis were reduced. This was associated with a 60% reduction in infarct size and marked improvement of systolic and diastolic cardiac performance as assessed with echocardiography and pressure volume loops. Fractionation studies revealed that only the fraction of the CM containing products >1000 kDa (100-220 nm) provided cardioprotection in a mouse model of ischemia and reperfusion injury. This indicates that the responsible paracrine factor of human MSCs is likely a large complex rather than a single small molecule. These data identify human MSC-CM as a promising therapeutic option to reduce myocardial infarct size in patients with acute MI and suggest that the use of stem cell secretions could extend the applicability of stem cells for therapeutic purposes.
Timmers
Leo
L
Department of Cardiology, University Medical Center Utrecht, Utrecht, the Netherlands.
Lim
Sai Kiang
SK
Arslan
Fatih
F
Armstrong
Jeffrey S
JS
Hoefer
Imo E
IE
Doevendans
Pieter A
PA
Piek
Jan J
JJ
El Oakley
Reida Menshawe
RM
Choo
Andre
A
Lee
Chuen Neng
CN
Pasterkamp
Gerard
G
de Kleijn
Dominique P V
DP
D000818:Animals; D053148:Caspase 3 / Q000032:analysis; D017077:Culture Media, Conditioned / Q000494:pharmacology*; D004195:Disease Models, Animal; D059630:Mesenchymal Stem Cells / Q000378:metabolism*; D009203:Myocardial Infarction / Q000628:therapy*; D015428:Myocardial Reperfusion Injury / Q000628:therapy; D018384:Oxidative Stress / Q000187:drug effects; D019899:Paracrine Communication; D051899:Smad2 Protein / Q000032:analysis; D013552:Swine; D016896:Treatment Outcome
D017077:Culture Media, Conditioned; D051899:Smad2 Protein; D053148:Caspase 3