Poor functional recovery after transplantation of diabetic bone marrow stem cells in ischemic myocardium

TY - JOUR

T1 - Poor functional recovery after transplantation of diabetic bone marrow stem cells in ischemic myocardium

AU - Govaert, Johannes A

AU - Swijnenburg, Rutger-Jan

AU - Schrepfer, Sonja

AU - Xie, Xiaoyan

AU - van der Bogt, Koen E A

AU - Hoyt, Grant

AU - Stein, William

AU - Ransohoff, Katherine J

AU - Robbins, Robert C

AU - Wu, Joseph C

PY - 2009/11

Y1 - 2009/11

N2 - 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.

AB - 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.

KW - Animals

KW - Bone Marrow Transplantation/methods

KW - Cardiovascular Diseases/surgery

KW - Cell Survival

KW - Coronary Vessels/surgery

KW - Diabetes Mellitus, Experimental/surgery

KW - Diabetic Angiopathies/surgery

KW - Disease Models, Animal

KW - Female

KW - Humans

KW - Male

KW - Mice

KW - Mice, Inbred C57BL

KW - Mice, Inbred Strains

KW - Myocardial Ischemia/surgery

KW - Reverse Transcriptase Polymerase Chain Reaction

KW - Stem Cell Transplantation/statistics & numerical data

KW - Transplantation, Autologous/physiology

U2 - 10.1016/j.healun.2009.06.018

DO - 10.1016/j.healun.2009.06.018

M3 - SCORING: Journal article

C2 - 19782602

VL - 28

SP - 1158

EP - 1165

JO - J HEART LUNG TRANSPL

JF - J HEART LUNG TRANSPL

SN - 1053-2498

IS - 11

ER -