Editors' ChoiceMyocardial Infarction

Therapeutic treasure hunt in the myeloid secretome

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Science Translational Medicine  28 Jan 2015:
Vol. 7, Issue 272, pp. 272ec15
DOI: 10.1126/scitranslmed.aaa5552

Treasures are rarely found in obvious places, and “X” almost never marks the spot. In an acute heart attack—myocardial infarction (MI)—occlusion of coronary arteries disrupts blood flow, causing myocardial cell death. Damage to the myocardium recruits inflammatory cells to the necrotic area, but this reparative process often leads to collagen-rich scar formation that interferes with heart function. Although rapid reperfusion therapy can limit the infarct area, in most cases massive myocardiocyte loss cannot be prevented. Autologous bone marrow cell (BMC) transfusion recently emerged as a therapy that can salvage oxygen-deprived heart tissue and reduce scar formation. But large variations in the success of BMC clinical trials have prevented its routine utility in MI patients. The contribution of BMCs to the formation of new cardiomyocytes is minor, suggesting that paracrine factors mediate the beneficial effects on the heart tissue. In a new study, Korf-Klingebiel and colleagues search for a secreted factor that might explain how BMCs heal the heart.

Using gene expression microarrays and bioinformatic analyses, the authors began their hunt in the secretome (a complete catalog of secreted proteins) of cells that home to ischemic heart tissue—chemokine receptor 4–expressing cells—from six MI patients undergoing intracoronary, autologous BMC transfusion. They analyzed 42 candidate proteins for their paracrine effects on myocytes and endothelial cells. Expression of one putative protein—an open reading frame on chromoseme 19—correlated with enhanced metabolic activity, suppression of apoptosis, and stimulation of cell proliferation. Renamed myeloid-derived growth factor (Mydgf), this protein’s expression was induced in the circulation and heart tissue after MI. Mydgf protein therapy (bolus injection into the damaged mouse hearts) significantly limited infarct size, myocardiocyte death, and scarring, and deletion of the Mydgf gene promoted these effects. Bone marrow transplantation demonstrated that this protein is indeed myeloid-born. Moreover, the healing effects of Mydgf were dependent on its secretion and on activation of prosurvival and antiapoptotic signaling pathways. Stimulation of cell proliferation required MAP kinases 1 and 3, signal transducer and activator of transcription–3 (STAT3), and cyclin D1. Future studies should strive to identify Mydgf receptor(s).

BMC transfusion therapy is associated with limited success, high cost, and serious safety issues. In this translational research treasure hunt, the authors reached their destination at the end of a clinically justified, data-intensive journey from patient-derived BMCs to a new paracrine growth factor that may provide a safer and superior therapeutic approach to MI.

M. Korf-Klingebiel et al., Myeloid-derived growth factor (C19orf10) mediates cardiac repair following myocardial infarction. Nat. Med. 10.1038/nm.3778 (2015). [Abstract]

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