The effect of age on the efficacy of human mesenchymal stem cell transplantation after a myocardial infarction.
OBJECTIVE
Clinical trials of cardiac cell therapy have indicated limited benefits in aging patients, even though preclinical studies using young animals consistently reported significant improvements. Animal studies have demonstrated reduced efficacy of donor cells isolated from older individuals. Here, we evaluated the effects of donor age on the function of human mesenchymal stem cells (hMSCs) in the context of cell therapy for ischemic cardiomyopathy.


METHODS
In vitro, we compared the growth and clonogenic potential of hMSCs isolated from young or old patients (1-5 vs. 50-70 years old). In vivo, we injected young or old hMSCs (2.0 x 10(6)) (or medium) into the infarcted myocardia of immunosuppressed rats immediately after coronary artery ligation (myocardial infarction [MI]). We assessed cardiac function (echocardiography) at 1, 2, and 4 weeks after MI, and myocardial matrix metalloproteinase-2 (MMP-2), MMP-9, and tissue inhibitor of matrix metalloproteinase-3 (TIMP-3) levels at 1 week.


RESULTS
In vitro, growth and colony-forming unit fibroblast (CFU-F) formation were markedly diminished in old hMSCs (p < 0.001 and p < 0.05, respectively, vs. young). In vivo, compared with old hMSCs or medium, young hMSCs best preserved ejection fraction, fractional shortening (p < 0.05), and left ventricular end-diastolic and end-systolic volumes (p < 0.01). Recipients of young hMSCs also exhibited increases in vascular density and TIMP-3 protein levels and activity (p < 0.05), and decreases in MMP protein levels and activity (p < 0.05).


CONCLUSIONS
The regenerative capacity of hMSCs was significantly influenced by age. Transplanting young hMSCs improved functional outcomes after an MI by preventing matrix degradation and promoting angiogenesis. The clinical implication is that aged patients require an optimized source of stem cells for treatment.
Fan
Ming
M
Division of Cardiovascular Surgery, Second Affiliated Hospital, Key Laboratories of Education Ministry for Myocardial Ischemia Mechanism and Treatment, Harbin Medical University, Harbin, China.
Chen
Wei
W
Liu
Wei
W
Du
Guo-Qing
GQ
Jiang
Shu-Lin
SL
Tian
Wei-Chen
WC
Sun
Lu
L
Li
Ren-Ke
RK
Tian
Hai
H
D000367:Age Factors; D000368:Aged; D000818:Animals; D001483:Base Sequence; D002675:Child, Preschool; D017931:DNA Primers; D004452:Echocardiography; D006801:Humans; D066298:In Vitro Techniques; D007223:Infant; D008297:Male; D059630:Mesenchymal Stem Cells / Q000166:cytology*; D008875:Middle Aged; D009203:Myocardial Infarction / Q000503:physiopathology / Q000601:surgery*; D018919:Neovascularization, Physiologic; D051381:Rats; D017208:Rats, Wistar; D020133:Reverse Transcriptase Polymerase Chain Reaction; D033581:Stem Cell Transplantation
D017931:DNA Primers