Gremlin-1 Drives Tumour Vascularization by Promoting Endothelial Differentiation and Angiogenesis

Gremlin-1 is a secreted antagonist of bone morphogenetic protein (BMP) signalling, highly expressed in various malignant tumours and is associated with poor prognosis. In addition to its established pro-angiogenic activity, its potential role in endothelial differentiation in tumour contexts remains incompletely defined. Here, we investigated whether gremlin-1 contributes to tumour vascularization by promoting both endothelial differentiation and vascular recruitment. The expression of gremlin-1 in murine embryonic stem cells (ESCs) promoted tumoroid development enriched in mesodermal and endothelial lineages in vitro, as indicated by the upregulation of lineage-specific markers and the presence of CD31-positive vascular-like networks. In vivo, gremlin-1-expressing ESCs generated larger teratomas with pronounced stromal expansion and increased vascularization, while retaining multilineage differentiation capacity. Using the chick chorioallantoic membrane (CAM) assay to discriminate donor-derived vasculogenesis from host-driven angiogenesis, we observed that gremlin-1-expressing grafts exhibited enhanced growth and vascularization. Species-specific endothelial labelling revealed the presence of both ESC-derived and host-derived endothelial cells within vascular structure. Collectively, our findings identify gremlin-1 as a regulator of tissue vascularization that integrates intrinsic endothelial differentiation with extrinsic angiogenic responses, a mechanism potentially relevant to vascular remodelling in several pathological conditions including tumour growth.