Myeloid-derived growth factor (MYDGF) is a secreted protein which belongs to the UPF0556 family. MYDGF was strongly expressed in spleen, prostate and lung, and weakly expressed in the left ventricle and liver. Bone marrow-derived monocyte and paracrine-acting protein promotes cardiac myocyte survival and adaptive angiogenesis for cardiac protection and/or repair after myocardial infarction (MI). MYDGF stimulates endothelial cell proliferation through a MAPK1/3-, STAT3- and CCND1-mediated signaling pathway. It inhibits cardiac myocyte apoptosis in a PI3K/AKT-dependent signaling pathway. MYDGF is involved in endothelial cell proliferation and angiogenesis. It may serve as a prototypical example for the development of protein-based therapies for ischemic tissue repair.