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

ABSTRACT: 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.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.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.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.

SUBMITTER: Govaert JA

PROVIDER: S-EPMC3163601 | biostudies-literature | 2009 Nov

REPOSITORIES: biostudies-literature

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

Govaert Johannes A JA Swijnenburg Rutger-Jan RJ Schrepfer Sonja S Xie Xiaoyan X van der Bogt Koen E A KE Hoyt Grant G Stein William W Ransohoff Katherine J KJ Robbins Robert C RC Wu Joseph C JC

The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation 20090926 11

<h4>Background</h4>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.<h4>Methods</h4>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 a ...[more]

PMID: 19782602

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Project description:Although bone marrow-derived mononuclear cells (BMNC) have been extensively used in cell therapy for cardiac diseases, little mechanistic information is available to support reports of their efficacy. To address this shortcoming, we compared structural and functional recovery and associated global gene expression profiles in post-ischaemic myocardium treated with BMNC transplantation. BMNC suspensions were injected into cardiac scar tissue 10 days after experimental myocardial infarction. Six weeks later, mice undergoing BMNC therapy were found to have normalized antibody repertoire and improved cardiac performance measured by ECG, treadmill exercise time and echocardiography. After functional testing, gene expression profiles in cardiac tissue were evaluated using high-density oligonucleotide arrays. Expression of more than 18% of the 11981 quantified unigenes was significantly altered in the infarcted hearts. BMNC therapy restored expression of 2099 (96.2%) of the genes that were altered by infarction but led to altered expression of 286 other genes, considered to be a side effect of the treatment. Transcriptional therapeutic efficacy, a metric calculated using a formula that incorporates both recovery and side effect of treatment, was 73%. In conclusion, our results confirm a beneficial role for bone marrow-derived cell therapy and provide new information on molecular mechanisms operating after BMNC transplantation on post ischemic heart failure in mice. We compared RNA samples extracted from whole hearts of infarcted mouse myocardium treated with bone marrow mononuclear cells control with untreated infarcted and control mice samples by analyzing hybridization to AECOM 32k mouse microarrays (http://microarray1k.aecom.yu.edu/) spotted with Operon version 3.0 70-mer oligonucleotides. The hybridization protocol and the slide type were uniform throughout the entire experiment to minimize the technical noise. Treated, control (sham) and infarcted red-labeled heart samples were hybridized against an in-house prepared green-labeled universal mouse reference.

Dataset Information

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

Publications

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

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