Therapies based on the proteins that are secreted by BMCs and that contribute to cardiac repair could be more reliable than BMC infusion itself. The investigators therefore characterized the transcriptome of BMCs from patients with acute MI, focussing on pro-angiogenic BMCs that express the chemokine receptor CXCR4. They identified 42 novel proteins that are predicted to be secreted. In subsequent functional screens, one of the candidates, MYDGF, was found to protect serum-starved rat cardiomyocytes from cell death and to promote angiogenesis in human endothelial cells. The function of MYDGF, which is encoded by an open reading frame on chromosome 19 (C19orf10), was previously unknown.
To explore the function and therapeutic potential of MYDGF, the investigators used a mouse model that simulates reperfusion therapy after MI. These mice had a temporary increase in Mydgf expression in the infarcted region, as did patients with acute MI. Mydgf-deficient mice were then generated and had no obvious phenotype under baseline conditions. However, following MI, increased cardiomyocyte death and decreased angiogenesis in the infarcted area were observed in Mydgf-deficient mice relative to wild-type mice. Mydgf-deficient mice subsequently developed larger infarcts and had more pronounced cardiac remodelling and systolic dysfunction than did wild-type mice. Mydgf secreted by bone marrow-derived cells is probably responsible, as transplantation of wild-type BMCs into Mydgf-deficient mice could rescue these effects.
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