Functional and Transcriptomic Recovery of Infarcted Mouse Myocardium Treated with Bone Marrow Mononuclear Cells

Abstract

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.

Evidence for Mechanisms Underlying the Functional Benefits of a Myocardial Matrix Hydrogel for Post-MI Treatment

“…By 1 week post-injection, the transcriptomes of saline and matrix-injected infarcts clustered separately. Similar analyses have also been applied to other experimental therapies for MI including cell transplantation (10–12) and injection of cell-derived products (13); however, to our knowledge, no other biologic-based therapy has been reported to induce a distinct transcription signature at a global level. In this study, the key modulated pathways included inflammation, reduction of apoptosis and cardiac hypertrophy, metabolism, and blood vessel and cardiac development (Central Illustration).…”

“…We showed an increase in PGC-1α in cardiomyocytes in matrix-injected animals. In comparison, injections of various bone marrow cells into the infarct myocardium have been associated with decreased expression of genes related to mitochondrial function (10,12). Angiotensin-converting enzyme inhibition using captopril, a common treatment for HF, similarly did not rescue changes in fatty acid metabolism (28).…”

Density Gradient Centrifugation Compromises Bone Marrow Mononuclear Cell Yield

“…It has been constantly described that this cell mixture promotes distinct angiogenic properties [2], mediates vascular repair, expresses several cytoprotective growth factors and cytokines [9] and restores pathologically altered genes after ischemic heart injury [10]. However, which component or combination of components exactly determines the efficacy of BMNCs is not entirely understood, hence impeding full realization and further advancement of the therapeutic concept [11].…”

Plasticity of the myelination genomic fabric

“…The novel computational tools introduced to quantify the genomic fabric besides our Prominent Gene Analysis and Transcriptomic Recovery Efficacy (Lachtermacher et al 2011;Soares et al 2011), represent powerful new additions to analyze microarray data.…”