Characterization of a Fetal Liver Cell Population Endowed with Long‐Term Multiorgan Endothelial Reconstitution Potential

• Published in: Stem cells (Dayton, Ohio) Ohio), 2017-02, Vol.35 (2), p.507-521
• Main Authors: Cañete, Ana, Comaills, Valentine, Prados, Isabel, Castro, Ana María, Hammad, Seddik, Ybot‐Gonzalez, Patricia, Bockamp, Ernesto, Hengstler, Jan G., Gottgens, Bertie, Sánchez, María José
• Format: Article
• Language: English
• Subjects: Animals; Antigens, CD - metabolism; Blood Vessels - transplantation; Bone marrow; Busulfan; Cadherins; Cadherins - metabolism; CD45 antigen; Cell Aggregation; Cell Line; Cells (biology); Circulation; Conditioning; Confinement; Developmental stages; Diseases; Endothelial Cells - cytology; Endothelial Cells - metabolism; Endothelial reconstitution; Endothelium; Extracellular Matrix Proteins - metabolism; Fetal liver; Fetus - cytology; Fetus - embryology; Fetuses; Functional integration; Gestation; Grafting; Grafts; Heart; Hematopoiesis; Hematopoietic progenitors; Hemopoiesis; Hepatocytes; Integration; Kidneys; Leukemia; Leukocyte Common Antigens - metabolism; Liver; Liver - embryology; Liver transplantation; Lungs; Mice; Microvasculature; Neonates; Newborn transplantation; Organ Specificity; Progenitor cells; Robustness; Rodents; Stem cell transplantation; Stem cells; T-Cell Acute Lymphocytic Leukemia Protein 1 - metabolism; Tissue‐Specific Stem Cells; Transplantation; Vascular diseases
• ISSN: 1066-5099; 1549-4918
• DOI: 10.1002/stem.2494

Stable reconstitution of vascular endothelial beds upon transplantation of progenitor cells represents an important challenge due to the paucity and generally limited integration/expansion potential of most identified vascular related cell subsets. We previously showed that mouse fetal liver (FL) hemato/vascular cells from day 12 of gestation (E12), expressing the Stem Cell Leukaemia (SCL) gene enhancer transgene (SCL‐PLAP+ cells), had robust endothelial engraftment potential when transferred to the blood stream of newborns or adult conditioned recipients, compared to the scarce vascular contribution of adult bone marrow cells. However, the specific SCL‐PLAP+ hematopoietic or endothelial cell subset responsible for the long‐term reconstituting endothelial cell (LTR‐EC) activity and its confinement to FL developmental stages remained unknown. Using a busulfan‐treated newborn transplantation model, we show that LTR‐EC activity is restricted to the SCL‐PLAP+VE‐cadherin+CD45− cell population, devoid of hematopoietic reconstitution activity and largely composed by Lyve1+ endothelial‐committed cells. SCL‐PLAP+ Ve‐cadherin+CD45− cells contributed to the liver sinusoidal endothelium and also to the heart, kidney and lung microvasculature. LTR‐EC activity was detected at different stages of FL development, yet marginal activity was identified in the adult liver, revealing unknown functional differences between fetal and adult liver endothelial/endothelial progenitors. Importantly, the observations that expanding donor‐derived vascular grafts colocalize with proliferating hepatocyte‐like cells and participate in the systemic circulation, support their functional integration into young livers. These findings offer new insights into the engraftment, phonotypical, and developmental characterization of a novel endothelial/endothelial progenitor cell subtype with multiorgan LTR‐EC activity, potentially instrumental for the treatment/genetic correction of vascular diseases. Stem Cells 2017;35:507–521 (A): SCL‐PLAP+VE‐cad+CD45−, Lyve1+/‐ (P+V+C−) fetal liver derived cells generate long term vascular endothelial clusters in different organs when intravenously transplanted into busulfan conditioned newborn recipient mice. P+V+C− cells contributed to endothelial cells (arrows) and also to rare blood cells (asterisks). Scale bars 50 μm. (B): As early as 3 weeks post‐transplantation, transferred fetal liver progenitor cells already form PLAP+ vascular clusters (vc) in the host