Poor functional recovery after transplantation of diabetic bone marrow stem cells in ischemic myocardium.
BACKGROUND
Autologous bone marrow mononuclear cell (BMMC) therapy has shown promise for improving cardiac function after myocardial infarction. The efficiency of such therapy for diabetic patients remains unknown.


METHODS
BMMCs were harvested from type 2 diabetic male BKS.Cg-m+/+Lepr(db)/J mice or C57BLKS/J (non-diabetic control) mice and were isolated using Ficoll-based separation. Cell characterization was performed by flow cytometry. Cell viability was determined by apoptosis and proliferation assays. Female BKS.Cg-m+/+Lepr(db)/J mice underwent left anterior descending artery ligation and were randomized into 3 groups receiving 2.5 x 10(6) diabetic BMMCs (n = 8), 2.5 x 10(6) control BMMCs (n = 8), or phosphate-buffered saline (n = 6). At Week 5, cardiac function was assessed with echocardiography and invasive hemodynamic measurements. Post-mortem cell survival was quantified by TaqMan real-time transcription polymerase chain reaction (RT-PCR) for the male Sry gene.


RESULTS
BKS.Cg-m+/+Lepr(db)/J BMMCs showed a significantly lower mononuclear fraction and a significantly lower proliferation rate compared with C57BLKS/J BMMCs. Fractional shorting (40.1% +/- 1.2% vs 30.3% +/- 1.9%; p = 0.001) and cardiac output (4,166 +/- 393 vs 2,246 +/- 462 microl/min; p = 0.016) significantly improved for mice treated with control BMMCs injection compared with those treated with diabetic BMMCs, respectively. This difference could not be attributed to difference in cell engraftment because TaqMan RT-PCR showed no significant difference in cell survival in infarcted hearts between the 2 groups.


CONCLUSIONS
Diabetic BMMCs are significantly impaired in their ability to improve cardiac function after myocardial infarction compared with control BMMCs. These findings could have significant clinical implication regarding autologous BMMC therapy in diabetic patients.
Department of Cardiothoracic Surgery, Stanford, CA 94305, USA.
Johannes A
JA
Govaert
Rutger-Jan
RJ
Swijnenburg
Sonja
S
Schrepfer
Xiaoyan
X
Xie
Koen E A
KE
van der Bogt
Grant
G
Hoyt
William
W
Stein
Katherine J
KJ
Ransohoff
Robert C
RC
Robbins
Joseph C
JC
Wu
D000818:Animals; D016026:Bone Marrow Transplantation / Q000379:methods*; D002318:Cardiovascular Diseases / Q000601:surgery; D002470:Cell Survival; D003331:Coronary Vessels / Q000601:surgery; D003921:Diabetes Mellitus, Experimental / Q000601:surgery*; D003925:Diabetic Angiopathies / Q000601:surgery*; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D017202:Myocardial Ischemia / Q000601:surgery*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D033581:Stem Cell Transplantation / Q000706:statistics & numerical data*; D014182:Transplantation, Autologous / Q000502:physiology*