MYDGF

MYDGF (originally C19orf10/SF20) is a secreted paracrine factor produced largely by bone marrow-derived monocytes and macrophages that promotes tissue survival, proliferation, and repair across cardiac, renal, and vascular contexts (PMID:25581518). It adopts a novel 10-stranded β-sandwich fold unlike known cytokines, and engages its receptor through a surface epitope centered on tyrosines Y71/Y73 and an adjacent loop (residues 97–101) (PMID:31772377). In the heart, MYDGF limits infarct scar and contractile dysfunction by supporting cardiomyocyte survival and angiogenesis after myocardial infarction (PMID:25581518), and drives cardiomyocyte proliferation and neonatal heart regeneration via the c-Myc/FoxM1 pathway (PMID:32802181). The protein converges on Akt-centered survival signaling in other tissues: it protects podocytes in diabetic kidney disease through Akt/BAD signaling, preserving nephrin and suppressing apoptosis (PMID:32588068), and it attenuates endothelial LDL transcytosis and atherosclerosis by suppressing MAP4K4 phosphorylation, enhancing Akt-1, and diminishing FoxO3a signaling (PMID:37767706). An earlier study under the SF20/IL-25 alias identified TSA-1 as a receptor mediating MYDGF-driven lymphoid cell proliferation (PMID:11714798). MYDGF localizes intracellularly in an ER/Golgi-consistent pattern prior to secretion (PMID:17362502).

1. 2001 Medium

   Before any defined receptor was known, this established that the secreted factor signals proliferation through a specific cell-surface receptor, TSA-1, on responsive cells.

   Evidence Receptor identification by forced TSA-1 expression in Ba/F3 cells and anti-TSA-1 antibody blocking of binding and proliferation

   PMID:11714798

   Open questions at the time

   • Single lab, no independent replication of the TSA-1 receptor assignment
   • Whether TSA-1 mediates MYDGF effects in non-lymphoid tissues is untested
   • No structural mapping of the ligand-receptor interface
2. 2007 Medium

   This clarified where the protein resides before secretion and which cells produce it in an inflamed tissue, framing it as a secreted product processed through the ER/Golgi.

   Evidence Antibody immunostaining of fibroblast-like synoviocytes and synovial tissue with cell-type co-staining, and competitive ELISA of synovial fluid

   PMID:17362502

   Open questions at the time

   • No functional consequence linked to the ER/Golgi localization
   • Cell-source identity differs from later macrophage-centric findings
   • Single-lab observation
3. 2015 High

   This assigned the first definitive in vivo biological function, showing the protein is a monocyte/macrophage-derived paracrine factor required to limit ischemic cardiac damage.

   Evidence Secretome bioinformatics, Mydgf knockout mouse MI model, recombinant protein rescue, and in vitro survival/angiogenesis assays

   PMID:25581518

   Open questions at the time

   • Receptor and downstream signaling in cardiac cells not defined here
   • Direct cardiomyocyte versus endothelial target not resolved
   • Molecular mechanism of survival/angiogenesis unspecified
4. 2019 High

   This resolved the molecular architecture, revealing a fold unlike known growth factors and pinpointing the surface residues required for receptor engagement.

   Evidence X-ray crystallography with neutralizing antibody epitope mapping and surface-patch mutagenesis coupled to functional activity assays

   PMID:31772377

   Open questions at the time

   • The cognate receptor for the Y71/Y73 epitope is not identified
   • No co-structure with any receptor
   • Relationship between this epitope and the earlier TSA-1 receptor is unaddressed
5. 2020 High

   These defined tissue-specific downstream pathways, linking MYDGF to c-Myc/FoxM1-driven cardiomyocyte proliferation and to Akt/BAD-mediated podocyte protection.

   Evidence Mydgf knockout and reporter mice, cardiac injury models with RNA-seq, plus DKD models with AAV gene transfer, recombinant protein, and Akt/BAD western blots in podocytes

   PMID:32588068 PMID:32802181

   Open questions at the time

   • The receptor coupling MYDGF to c-Myc/FoxM1 and Akt/BAD is not identified
   • Cell source shifts to endothelial cells in neonatal heart, mechanism of this switch unknown
   • Direct versus indirect activation of these pathways not dissected
6. 2023 High

   This extended MYDGF function to vascular protection, showing it suppresses endothelial LDL transcytosis and atherosclerosis through a MAP4K4/Akt-1/FoxO3a axis.

   Evidence Monocyte/macrophage-targeted Mydgf knockout on Ldlr-/- background, bone marrow transplantation, macrophage overexpression, endothelial-macrophage co-culture, and pathway western blots

   PMID:37767706

   Open questions at the time

   • The receptor linking MYDGF to MAP4K4 suppression is unknown
   • Whether the Akt convergence across tissues reflects a single receptor is untested
   • Direct biochemical effect on MAP4K4 not established

• The receptor(s) that transduce MYDGF signaling in cardiac, renal, and vascular cells, and how they relate to the surface epitope and the lymphoid TSA-1 receptor, remain unresolved.
• No receptor identified for the Y71/Y73 epitope outside the lymphoid TSA-1 context
• No co-structure of MYDGF with any receptor
• Mechanism unifying Akt/c-Myc/FoxM1/MAP4K4 outputs is unknown