Enhanced Hematovascular Contribution of SCL 3′ Enhancer Expressing Fetal Liver Cells Uncovers Their Potential to Integrate in Extramedullary Adult Niches

Abstract

Fetal liver (FL) hematopoietic progenitors have superior blood engraftment competence compared with adult bone marrow (BM), however less is known about FL in vivo vascular capacity. Here we show in transplantation assays that FL cells possess enhanced vascular endothelial potential compared with adult bone marrow. We generated high-level hematopoietic chimeras using donor cells from mice transgenic for the stem cell leukaemia 3' enhancer human placental alkaline phosphatase (SCL3'Enh-PLAP) reporter construct, active in vascular endothelium, and blood progenitor and stem cells. Long-term lineage tracing analysis revealed PLAP(+) vascular-like patches in FL-derived chimeras, whereas adult BM-derived chimeras presented only rare and scattered PLAP(+) cells. PLAP(+) vascular-like patches were formed following transplantation into both newborn and adult recipient mice, although their frequency was reduced in adult recipients. Confocal analysis of multiple labeled tissues revealed that whereas most liver and heart PLAP(+) vascular patch-associated cells were endothelial, PLAP(+) vascular patches in the kidney contained endothelial, hematopoietic, and putative hemangioblastic cells. Moreover, fluorescence-activated cell sorting assays showed that only FL PLAP(bright+) donor cells can generate PLAP(+) vascular patches upon transplantation. Taken together, these data demonstrate superior vascular contribution potential of FL cells, and not only provide new insights into the developmental pathways controlling endothelial development but also may prove informative when addressing the mechanisms involved in vascular regeneration and hemangiogenic recovery in a clinical context.